Cognitive composite parameters and uses thereof for evaluating multiple sclerosis

ABSTRACT

Methods, systems and kits for the identification, assessment and/or treatment of a subject having multiple sclerosis are disclosed.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.61/636,291, filed Apr. 20, 2012, the contents of which are incorporatedherein by reference in their entirety.

BACKGROUND OF THE INVENTION

Multiple sclerosis (MS) is an inflammatory disease of the brain andspinal cord characterized by recurrent foci of inflammation that lead todestruction of the myelin sheath. In many areas, nerve fibers are alsodamaged. Inflammatory activity in MS patients tends to be highest in theinitial phase of disease.

Data have demonstrated that irreversible axonal loss occurs early in thecourse of MS. Transected axons fail to regenerate in the central nervoussystem (CNS); and therefore, early treatment aimed at suppressing MSlesion formation is of significant importance. As early as diseaseonset, axons are transected in lesions with active inflammation (Trappet al. (1998) N Engl J Med 338: 278-285; Bjartmar et al. (2001) CurrOpin Neurol 14: 271-278; Ferguson et al. (1997) Brain 120: 393-399). Thedegree of demyelination is related to the degree of inflammation and theexposure of demyelinated axons to the inflammatory environment, as wellas non-inflammatory mediators (Trapp et al. (1998) N Engl J Med 338:278-285; Kornek et al. (2000) Am J Pathol 157: 267-276; Bitsch et al.(2000) Brain 123: 1174-1183). There is also destruction ofoligodendrocytes with impaired remyelination in demyelinating lesions(Peterson et al. (2002) J Neuropathol Exp Neurol 61: 539-546; Chang etal. (2002) N Engl J Med 346: 165-173). The loss of oligodendrocytesleads to a reduction in the capacity to re-myelinate and may result inthe loss of trophic factors that support neurons and axons (Bjartmar etal. (1999) J Neurocytol 28: 383-395).

MS-mediated damage to the brain and spinal cord causes not only physicaldisabilities, but also significant cognitive impairment. Despite thesignificant impact that cognitive impairments have on the overalldisability and quality of life of MS patients, adequate tools for theassessment of MS-associated cognitive impairments are needed. Currenttest batteries for assessment of cognitive impairment often require apanel of lengthy, cumbersome tests many of which are not pertinent tothe disease itself and that require administration and interpretation bytrained neuropsychologists.

Therefore, there is a need to establish a practical and valid cognitivemeasurement tool for use in MS patient evaluation, which are not onlytailored to assess the cognitive domains affected by MS, but are alsoefficient, and easily administered with cross-cultural utility.

SUMMARY OF THE INVENTION

The present invention provides, at least in part, methods, systems andkits for the identification, assessment and/or treatment of a subjecthaving a neurological disorder, e.g., multiple sclerosis (MS). In oneembodiment, the methods, systems and kits include the step of detectingand/or quantifying a cognitive impairment in the subject (e.g., an MSpatient), by obtaining a composite cognitive endpoint that includes ameasure of processing speed and a measure of learning and memory(referred to herein as an “attention factor” and a “memory factor,”respectively). Composite cognitive endpoints offer several advantagesover current methodologies, including, but not limited to, increasedsensitivity, enhanced statistical power, smaller sampling size andenhanced simplicity. The invention can, therefore, be used, for example,for one or more of: (i) diagnosing, prognosing and/or evaluating, asubject (e.g., an MS patient); (ii) evaluating responsiveness to, ormonitoring, a therapy (e.g., an MS therapy); (iii) identifying a patientas being stable, or showing improvement or disease progression; (iv) tostratify a subject (e.g., an MS patient or patient population) as beinga disease non-progressor or a disease progressor; and/or (v) moreeffectively monitoring, treating multiple sclerosis, or preventingworsening of disease and/or relapses.

Accordingly, in one aspect, the invention features a method ofevaluating (e.g., evaluating and/or quantifying cognitive function orimpairment in) a subject (e.g., a patient, a patient group or a patientpopulation), having a neurological disorder (e.g., multiple sclerosis(MS)), or at risk of developing the neurological disorder. The methodincludes acquiring a value of a composite parameter from the subject,said composite parameter including an attention factor and a memoryfactor, thereby evaluating the subject. In one embodiment, the subjecthas MS, e.g., is an MS patient who has undergone or is undergoingtreatment with one or more MS therapies.

In a related aspect, the invention features a method of detecting and/orquantifying a cognitive impairment in a subject (e.g., a patient, apatient group or a patient population), having multiple sclerosis (MS),or at risk of developing MS. The method includes acquiring a value of acomposite parameter from the subject, said composite parameter includingan attention factor and a memory factor, e.g., a first value forattention and/or processing speed (PS) factor and a second value for amemory factor, thereby detecting and/or quantifying the cognitiveimpairment in the subject. In one embodiment, the subject has MS, e.g.,is an MS patient who has undergone or is undergoing treatment with an MStherapy (e.g., one or more MS therapies). The cognitive impairmenttested and/or quantified can be used in making treatment decisions.

In some embodiments, responsive to a determination of the value of thecomposite parameter using the aforesaid methods, the method furtherincludes one or more of the following:

(i) identifying the subject as being in need of a therapy, e.g., an MStherapy (e.g., a first MS therapy or a second (alternative) MS therapy);

(ii) identifying the subject as having an increased or a decreasedresponse to a therapy, e.g., an MS therapy (e.g., a first MS therapy ora second (alternative) MS therapy);

(iii) identifying the subject as being stable, showing an improvement incognitive abilities (e.g., as being a disease non-progressor), orshowing a decline in cognitive abilities (e.g., as being a diseaseprogressor);

(iv) diagnosing, and/or prognosing the subject;

(v) determining a therapy (e.g., an MS therapy), e.g., selecting oraltering the course of, a therapy or treatment, a dose, a treatmentschedule or time course, and/or the use of an alternative MS therapy);

(vi) determining a time course of disease progression (e.g., MS diseaseprogression) in the subject; and/or

(vii) administering a therapy, e.g., an MS therapy (e.g., a first MStherapy or a second (alternative) MS therapy) to the subject).

In one embodiment, one or more of (i)-(vii) are effected in response tothe value of the composite parameter. A change (e.g., an increased or adecrease) in the value of the composite parameter relative to aspecified parameter indicates one or more of: identifies the subject asbeing in need of the therapy (e.g., an MS therapy (e.g., a first MStherapy or a second (alternative) MS therapy); identifies the subject ashaving an increased or decreased response to the therapy; determines thetreatment to be used; and/or determines or predicts the time course ofthe disease (e.g., the MS disease).

In one embodiment, an increase in the value of the composite parameter,relative to the specified parameter, is indicative of improved cognitivefunction (or decreased cognitive impairment) in the subject.

In one embodiment, a decrease in the value of the composite parameter,relative to the specified parameter, is indicative of decreasedcognitive function (or increased cognitive impairment) in the subject.

In another aspect, the invention features a method for identifying asubject (e.g., a patient, a patient group or population), having MS, orat risk for developing MS, as having an increased or a decreasedresponse to an MS therapy. The method includes acquiring a value of acomposite parameter from the subject, said composite parameter includingan attention factor and a memory factor, e.g., a first value forattention and/or processing speed (PS) factor and a second value for amemory factor, and responsive to said value, identifying the subjecthaving MS, or at risk for developing MS, as being responsive or lessresponsive to the MS therapy.

In one embodiment, the method includes comparing the value of thecomposite parameter to a specified parameter (e.g., a reference value asdescribed herein).

In one embodiment, a decreased value of the composite parameter relativeto a specified parameter indicates that the subject is less responsiveto the MS therapy. For example, a value of at least 0.2, 0.3, 0.4, 0.5,0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, or 1.5 SD, lower than thespecified parameter indicates that the subject has increased cognitiveimpairment, and thus the subject is being less responsive to the MStherapy.

In one embodiment, a decreased value of the composite parameter of atleast 0.5 SD relative to a specified parameter indicates that thesubject has experienced a cognitive impairment (e.g., a clinicallysignificant cognitive impairment). Such subject can be at risk ofexperiencing significant disability.

In one embodiment, a decreased value of the composite parameter of atleast 1.0 SD relative to a specified parameter indicates that thesubject has experienced a cognitive impairment (e.g., a clinicallysignificant cognitive impairment). Such subject can have developedsignificant disability.

In other embodiments, a stable or increased value of the compositeparameter relative to a specified parameter indicates that the subjectis stable or has improved cognitive function, and thus the subject isbeing responsive to the MS therapy.

In other embodiments, an increased value beyond that of the expectedpractice effect on the composite parameter indicates that the subjecthas restoration of damaged cognitive function. In certain embodiments,the subject with said increased value can be responsive to a reparativeMS therapy (e.g. a remyelinating CNS agent).

In another aspect, the invention features a method of evaluating ormonitoring an MS therapy in a subject (e.g., a patient, a patient groupor population), having MS, or at risk for developing MS. The methodincludes:

acquiring a value (e.g., a baseline value) of a composite parameter fromthe subject, said composite parameter including an attention factor anda memory factor, e.g., a first value for attention and/or processingspeed (PS) factor and a second value for a memory factor, and

(optionally) responsive to said value, treating, selecting and/oraltering one or more of the course of the MS therapy, the dosing of theMS therapy, the schedule or time course of the MS therapy, oradministration of a second, alternative MS therapy.

In one embodiment, the method includes comparing the value of thecomposite parameter to a specified parameter (e.g., a reference value asdescribed herein). In certain embodiments, the sample is obtained atdifferent time intervals, e.g., prior to, during, or after treatmentwith the MS therapy.

In one embodiment, a decreased value of the composite parameter relativeto a specified parameter indicates that the subject is progressing inthe disorder. For example, a value of at least 0.2, 0.3, 0.4, 0.5, 0.6,0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, or 1.5 SD, lower than thespecified parameter indicates that the subject has increased cognitiveimpairment, thus showing disease progression.

In other embodiments, a stable or an increased value of the compositeparameter relative to a specified parameter indicates that the subjectis stable or has an improved prognosis and/or outcome to the MS therapy.

The method can be used, e.g., to evaluate the suitability of, or tochoose between alternative treatments, e.g., a particular dosage, modeof delivery, time of delivery.

In yet another aspect, the invention features a method of evaluating asubject's prognosis or MS disease progression, in a subject (e.g., apatient, a patient group or population), having MS, or at risk fordeveloping MS. The method can be a diagnostic or prognostic method. Themethod includes:

acquiring a value of a composite parameter from the subject, saidcomposite parameter including an attention factor and a memory factor,e.g., a first value for attention and/or processing speed (PS) factorand a second value for a memory factor, thereby evaluating the subject;and

(optionally) comparing the value of the composite parameter to aspecified parameter (e.g., a reference value as described herein).

In certain embodiments, the sample is obtained at different timeintervals, e.g., prior to, during, and/or after treatment with the MStherapy.

In one embodiment, a decreased value of the composite parameter relativeto a specified parameter indicates that the subject is progressing inthe disorder. For example, a value of at least 0.2, 0.3, 0.4, 0.5, 0.6,0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, or 1.5 SD, lower than thespecified parameter indicates that the subject has increased cognitiveimpairment, thus showing disease progression.

In other embodiments, a stable or an increased value of the compositeparameter relative to a specified parameter indicates a stable orimproved diagnosis or prognosis of the subject.

In other embodiments, any of the aforesaid methods further includetreating, or preventing in, a subject having MS one or more symptomsassociated with MS. In certain embodiments, the treatment includesreducing, retarding, or preventing, a relapse, or the worsening of adisability, in the MS subject. In one embodiment, the method includes,responsive to the value of the composite parameter, administering to thesubject a therapy for MS (also referred to herein as an “MS therapy” or“MS treatment”), in an amount sufficient to reduce one or more symptomsassociated with MS.

In yet another aspect, the invention features a method of treating orpreventing one or more symptoms associated with MS, in a subject havingMS, or at risk for developing MS. The method includes:

acquiring a value of a composite parameter from the subject, saidcomposite parameter including an attention factor and a memory factor,e.g., a first value for attention and/or processing speed (PS) factorand a second value for a memory factor;

responsive to said value, performing one or more of: administering to asubject an MS therapy, in an amount sufficient to reduce one or moresymptoms associated with MS;

selecting and/or altering a dosing of an MS therapy;

selecting and/or altering the schedule or time course of an MS therapy;

selecting and/or administering an alternative MS therapy;

selecting and/or administering a therapy for cognitive and/or memoryimpairment (e.g., administering one or more of: an agent that increasesthe level of neurotransmitters in the brain, NMDA receptor agents,and/or CNS stimulants (e.g., dextro or levo amphetamines); and/or

selecting and/or administering a therapy for improving attention and/orprocessing speed, thereby treating or preventing MS in the subject.

In certain embodiments, in response to an increased value of saidcomposite parameter relative to a reference value, the MS treatment isinitiated or continued; and in response to a decreased value of saidcomposite parameter relative to a reference value, the MS treatment ismodified (e.g., an alternative MS therapy is used).

In certain embodiments, the MS therapy comprises one or more of anIFN-β1 molecule; a polymer of four amino acids found in myelin basicprotein, e.g., a polymer of glutamic acid, lysine, alanine and tyrosine(e.g., glatiramer (Copaxone®)); an antibody or fragment thereof againstalpha-4 integrin (e.g., natalizumab (Tysabri®)); an anthracenedionemolecule (e.g., mitoxantrone (Novantrone®); or fingolimod (FTY720;Gilenya®); a dimethyl fumarate (e.g., an oral dimethyl fumarate(BG-12)); an antibody to the alpha subunit of the IL-2 receptor of Tcells (e.g., Daclizumab); a reparative therapy; an anti-LINGO-1antibody; or an inhibitor of a dihydroorotate dehydrogenase (e.g.,teriflunomide).

In one embodiment, the IFNβ1 molecule is an IFN-β1a agent (e.g.,Avonex®, Rebif®). In another embodiment, the IFNβ1 molecule is anINF-β1b agent (e.g., Betaseron®, Betaferon®).

In another embodiment, the IFN-β1 molecule comprises one or more of anIFN-β1a or IFN-β1b polypeptide, a variant, a homologue, a fragment or aderivative thereof (e.g., a pegylated variant thereof).

In one embodiment, the MS therapy includes an antibody or fragmentthereof against alpha-4 integrin (e.g., natalizumab (Tysabri®)).

In certain embodiments, the method of treatment includes administrationof an MS therapy (e.g., a first MS therapy). In another embodiment, theMS therapy is a second or an alternative therapy (e.g., a therapyselected when a patient is less responsive or shows disease progressionwhen treated with the first therapy).

In one embodiment, the first therapy is chosen from one or more of:

an IFNβ agent (e.g., an IFN-β1a molecule or an IFN-β1b molecule,including analogues and derivatives thereof (e.g., pegylated variantsthereof));

a polymer of four amino acids found in myelin basic protein, e.g., apolymer of glutamic acid, lysine, alanine and tyrosine (e.g., glatiramer(Copaxone®));

an antibody against CD52 (e.g., alemtuzumab (Lemtrada®)); or

an inhibitor of a dihydroorotate dehydrogenase (e.g., teriflunomide).

In certain embodiments, the MS therapy is an alternative or secondtherapy to the first MS therapy. In one embodiment, the alternativetherapy includes an antibody or fragment thereof against alpha-4integrin (e.g., natalizumab (Tysabri®). In yet other embodiments, thealternative therapy includes an anthracenedione molecule (e.g.,mitoxantrone (Novantrone®)). In yet another embodiment, the alternativetherapy includes a fingolimod (e.g., FTY720; Gilenya®). In oneembodiment, the alternative therapy is a dimethyl fumarate (e.g., anoral dimethyl fumarate (BG-12)). In other embodiments, the alternativetherapy is an antibody to the alpha subunit of the IL-2 receptor of Tcells (e.g., Daclizumab). In another embodiment, the alternative therapyincludes a reparative therapy. In yet another embodiment, thealternative therapy includes an anti-LINGO-1 antibody. In oneembodiment, the alternative therapy includes an inhibitor of adihydroorotate dehydrogenase (e.g., teriflunomide).

In certain embodiments, the method further includes the use of one ormore symptom management therapies, such as antidepressants, analgesics,anti-tremor agents, among others.

In other embodiments, the method includes step of administering the useof one or more therapies for management of cognitive and/or memoryimpairment. Examples of such therapies include, but are not limited to,agents that increase the level of neurotransmitters in the brain, NMDAreceptor agents, and CNS stimulants such as dextro- orlevo-amphetamines.

Additional embodiments or features of any of the foregoing methods areas follows:

Value of Composite Parameter

In certain embodiments, the value of the composite parameter used in themethods and systems described herein is compared to a specifiedparameter (e.g., a reference value, such as value obtained from at leastone of: a healthy subject or an average of healthy subjects; the subjectat different time intervals (e.g., prior to, during, or after the MStherapy); a group of MS patients having the same or different diseaseprogressions; the group of MS patients having the same or differentdisease progressions at different time intervals; a group of MS patientsundergoing different MS treatments than the subject; or a group of MSpatients undergoing the same MS treatment as the subject. In certainembodiments, the subject is monitored in one or more of the followingperiods:

prior to beginning of treatment; during the treatment; after thetreatment has been administered; or at a first and second time points atleast 1, 2, 3, 4, 5, or 6 months apart.

In one embodiment, the specified parameter, e.g., the reference value is0. The value of the composite parameter can range from −0.1 to −2 in asubject with MS. In one embodiment, an increase in the value of thecomposite parameter, relative to the specified parameter, is indicativeof improved cognitive function in the subject. For example, an increasein the value of the composite parameter, relative to the referencevalue, by at least 5%, 10%, 20%, 30%, 40%, 50%, or 0.2 to 1.5 SD, ormore is indicative of improved cognitive function in the subject.

In another embodiment, a decrease in the value of the compositeparameter, relative to the specified parameter, is indicative ofdecreased cognitive function in the subject. For example, a value of atleast 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4,or 1.5 SD, lower than, the specified parameter indicates that thesubject has increased cognitive impairment. In other embodiments, adecrease in the value of the composite parameter, relative to thereference value, by at least 5%, 10%, 20%, 30%, 40%, 50%, or 0.2 to 1.5SD, or more is indicative of decreased cognitive function in thesubject. In certain embodiments, a composite value of −1.5 or −1.0 SDbelow a reference value is indicative of cognitive impairment.

In certain embodiments, the value of the composite parameter isdifferent in subjects with different MS diagnoses. For example, thevalue of the composite parameter is higher in an MS patient havingrelapse remitting multiple sclerosis (RRMS) compared to an MS patientwith secondary progressive multiple sclerosis (SPMS).

In certain embodiments, the value of the composite parameter isindicative of cognitive function in a domain including one or more ofinformation processing speed, information processing efficiency, visualmemory, verbal memory (e.g., memory acquisition), executive function orperceptual processing.

In one embodiment, the value of the composite parameter is acquired byevaluating one, two, three, four or more attention and memory factors.

Memory factors can include one or more verbal or visual memory factors.

Exemplary tests for evaluating memory factors include, but are notlimited to, tests for evaluating one or more of auditory memory, verballearning and/or remembering visual information (e.g., SelectiveReminding Test (SRT)); tests for evaluating auditory/verbal memory(e.g., California Verbal Learning Test Second Edition (CVLT2)), or theRey Auditory Verbal Learning Test (RAVLT); and tests for evaluatingvisual/spatial memory (e.g., Brief Visuospatial Memory Test Revised(BVMTR)).

Exemplary tests for evaluating attention, e.g., processing speed and/orworking memory, include but are not limited to, tests for evaluating oneor more of working memory, processing speed (e.g., auditory informationprocessing speed), flexibility or calculation ability (e.g., PacedAuditory Serial Addition Test (PASAT)); and tests for evaluating complexscanning and/or visual tracking (e.g., Symbol Digit Modalities Test(SDMT)).

In certain embodiments, the attention and memory factors are obtained byadministering one, two, three, four or more of:

(i) an assessment of processes involved in learning and/or rememberingvisual information (e.g., Selective Reminding Test (SRT)),

(ii) an assessment of visuospatial memory (e.g., Brief Visual/spatialMemory Test (BVMT)),

(iii) an assessment of complex scanning and/or visual tracking (e.g.,Symbol Digit Modalities Test (SDMT), or

(iv) an assessment of one or more of auditory information processingspeed, flexibility or calculation ability (e.g., Paced Auditory SerialAddition Test (PASAT)).

The assessments described herein can be administered simultaneously orwithin the same evaluation interval in the subject. In some embodiments,the evaluation interval refers to two or more assessments administeredat two or more time points to obtain the value of the compositeparameter.

Z Scores/Factor Construction

In certain embodiments, the value of the composite parameter used in themethods described herein is an average value of one or more memoryfactors and one or more attention factors.

In certain embodiments, the value of the composite parameter includes afirst value for an attention and/or processing speed (PS) factor and asecond value for a memory factor, wherein:

(i) the first value is acquired by obtaining a score, e.g., astandardized score, from at least two assessments indicative ofattention and/or processing speed, and

(ii) the second value is acquired by obtaining a score, e.g., astandardized score, from at least one assessment of auditory/verballearning and memory, and at least one assessment of visual learning andmemory.

In some embodiments, the first value is obtained by one or more of:

(i) averaging the scores from at least one assessment of complexscanning and/or visual tracking, and at least one or two assessment(s)of processing speed, flexibility and/or calculation ability;

(ii) as a function of a score based on a Symbol Digit Modalities Test(SMDT)) and a score based on at least one or two Paced Auditory SerialAddition Test (PASAT); or

(ii) calculating the first value using the following equation:

{SMDT score+[PASAT 3 score+PASAT 2 score]/2)}/2.

In some embodiments, the second value is obtained by one or more of:

(i) averaging the scores from at least one or two assessments indicativeof verbal learning and delayed recall, combined with at least one or twoassessments indicative of visual learning and delayed recall;

(ii) averaging the scores at least one or two components of a SelectiveReminding Test (SRT) and at least one or two components of a BriefVisuospatial memory Test (BVMT); or

(iii) calculating the second value using the following equation:

[SRT learning score+SRT delay score+BVMT learning score and BVMT delayscore]/4.

The first and the second values can be weighed equally (e.g., 50:50) ingenerating the value of the composite parameter, or differentially,e.g., said first or second value being about 10%, 20%, 25%, 30%, 40%,60%, 75% or more the value of the other value, in generating the valueof the composite parameter.

In yet other embodiments, the scores from the assessments used to obtainthe second value are weighed equally, or differentially, e.g., saidfirst or second value being about 10%, 20%, 25%, 30%, 40%, 60%, 75% ormore the value of the other value, in generating the value of thecomposite parameter.

In other embodiments, the scores from the assessments of verbal andvisual memory are weighed equally, or differentially as describedherein. The scores from the assessments of learning and delayed recallcomponents can be weighed equally or differentially as described herein.

In yet other embodiments, the scores from the at least one assessment ofcomplex scanning and/or visual tracking, and the at least one or twoassessment(s) of processing speed, flexibility and/or calculationability are weighed equally, or differentially, e.g., said first orsecond value being about 10%, 20%, 25%, 30%, 40%, 60%, 75% or more thevalue of the other value, in generating the value of the compositeparameter.

In one embodiment, the value of the attention factor is evaluated by aobtaining a score of the average of the sum of an assessment of complexscanning and/or visual tracking and the average of at least twoassessments of auditory information processing speed, flexibility orcalculation ability; or {SMDT+[PASAT 3+PASAT 2]/2)}/2.

In other embodiments, the value of the verbal memory factor is evaluatedby a obtaining a score of the average of the sum of at least twoassessments of processes involved in learning and/or remembering visualinformation; or (SRT Total Learning+SRT Delayed Recall)/2.

In yet other embodiments, the value of the visual memory factor isevaluated by a obtaining a score of the average of at least twoassessments of visuospatial memory; or (BVMT Total Recall+BVMT DelayedRecall)/2.

In other embodiments, the value of the memory factor is the average ofthe value of the verbal memory factor and the visual memory factor.

In other embodiments, the value of the composite parameter has areliability of at least 0.65, 0.69, 0.70, 0.75, 0.80, 0.85, 0.90 orhigher.

In other embodiments, the scores used to generate the composite areadjusted, e.g., demographically adjusted, thus providing a standardizedscore.

In other embodiments, the value of the composite parameter comprises ascore value chosen from one or more of: −0.6 to −1.6 for SDMT, −0.2 to−1.2 for PASAT 3, −0.12 to −1.12 for PASAT 2, −0.25 to −1.25 for SRTTotal, −0.3 to −1.3 for SRT Delay, −0.8 to −1.8 for BVMT-R Total, or−1.2 to −2.2 for BVMTR Delay.

Subjects

For any of the methods disclosed herein, the subject treated, or thesubject from which the value is obtained, is a subject having, or atrisk of having MS at any stage of treatment. In certain embodiments, theMS patient is chosen from a patient having one or more of: Benign MS,RRMS (e.g., quiescent RRMS, active RRMS), primary progressive MS, orsecondary progressive MS. In one embodiment, the subject isasymptomatic. In other embodiments, the subject has one or more MS-likesymptoms, such as those having clinically isolated syndrome (CIS) orclinically defined MS (CDMS). In one embodiment, the subject is an MSpatient (e.g., a patient with RRMS or SPMS) prior to administration ofan MS therapy described herein. In one embodiment, the subject is anewly diagnosed or an undiagnosed RRMS or SPMS patient. In anotherembodiment, the subject is an MS patient (e.g., an RRMS patient) afteradministration of an MS therapy described herein. In other embodiments,the subject is an MS patient after administration of the MS therapy forone, two weeks, one month, two months, three months, four months, sixmonths, one year or more.

In certain embodiments, the subject is a patient having one of: benignMS; relapse/remitting MS (RRMS, e.g., quiescent RRMS, active RRMS);primary progressive MS; secondary progressive MS (SPMS); clinicallyisolated syndrome (CIS); or clinically defined MS (CDMS). In oneembodiment, the subject has RRMS (e.g., quiescent RRMS, active RRMS). Inother embodiments, the subject has secondary progressive MS (SPMS).

The methods described herein can be used to distinguish MS patients,e.g., to distinguish between RRMS and SPMS.

Timing of Assessment

In one embodiment, the methods described herein include comparing thevalue of the composite parameter to a specified parameter (e.g., areference value as described herein). A value can be analyzed at anystage of treatment, for example, prior to, during, or after terminating,administration of the MS therapy, to thereby determine appropriatedosage(s) and MS therapy (e.g., amount per treatment or frequency oftreatments) for prophylactic or therapeutic treatment of the subject. Incertain embodiments, the methods include the step of acquiring the valueof the composite parameter from the subject, prior to, or after,administering the MS therapy, to the subject.

In one embodiment, the value of the composite parameter is assessed atpre-determined intervals, e.g., a first point in time and at least at asubsequent point in time. For example, the first and subsequent timepoints are evaluated at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,or 12 months apart; e.g., typically between 1 to 8, 2 to 7, 3 to 6,months apart.

In one embodiment, a time course is measured by determining the timebetween significant events in the course of a patient's disease, whereinthe measurement is predictive of whether a patient has a long timecourse. In another embodiment, the significant event is the progressionfrom primary diagnosis to death. In another embodiment, the significantevent is the progression from primary diagnosis to worsening disease. Inanother embodiment, the significant event is the progression fromprimary diagnosis to relapse. In another embodiment, the significantevent is the progression from secondary MS to death. In anotherembodiment, the significant event is the progression from remission torelapse. In another embodiment, the significant event is the progressionfrom relapse to death. In certain embodiments, the time course ismeasured with respect to one or more overall survival rate, time toprogression and/or using the EDSS or other assessment criteria.

In one embodiment, the value of the composite parameter is assessed inan MS patient prior to administration of an MS therapy described herein.For example, the value of the composite parameter is assessed in a newlydiagnosed MS patient. In another embodiment, the value of the compositeparameter is assessed in an MS patient after administration of an MStherapy described herein (e.g., after administration of the MS therapyfor one, two weeks, one month, two months, three months, four months,six months, one year or more).

In certain embodiments, a pre-determined measure or value is createdafter evaluating the sample by dividing subject's samples into at leasttwo patient subgroups (e.g., progressors vs. non-progressors). Incertain embodiments, the number of subgroups is two, such that thepatient sample is divided into a subgroup of patients having a specifiedvalue of the composite parameter described herein, and a subgroup nothaving the specified value of the composite parameter. In certainembodiments, the number of subgroups is greater than two, including,without limitation, three subgroups, four subgroups, five subgroups andsix subgroups, depending on stratification of predicted MS therapyefficacy as correlated with particular value of the composite parameter.

In one embodiment, the subject is treated with a first MS therapy (e.g.,an interferon, glatiramer (Copaxone®), Daclizumab), and shows a value inthe range of responsiveness described herein (thus, indicating that thesubject evaluated is responsive to the first MS therapy). A value in therange of non-responsiveness described herein indicates that the subjectevaluated is less responsive to the first MS therapy, and thus, analternative, second MS therapies can be considered, including, but notlimited to, natalizumab (Tysabri®), mitoxantrone (Novantrone®),fingolimod (FTY720; Gilenya®), dimethyl fumarate (e.g., an oral dimethylfumarate (BG-12)), alemtuzumab (Lemtrada®)), or an anti-LINGO-1antibody.

Combination with Other Tests

The methods of the invention can further include the step of monitoringthe subject, e.g., for a change (e.g., an increase or decrease) in oneor more of: levels of one or more MS biomarkers; the rate of appearanceof new lesions, e.g., in an MRI scan; the appearance of newdisease-related symptoms; a change in EDSS score; a change in quality oflife; or any other parameter related to clinical outcome.

In one embodiment, the methods described herein further include one ormore steps of: performing a neurological and/or neuropsychologicalevaluation, evaluating the subject's status on the Expanded DisabilityStatus Scale (EDSS), or detecting the subject's lesion status (e.g., asassessed using an MRI).

The subject can be monitored in one or more of the following periods:prior to beginning of treatment; during the treatment; or after thetreatment has been administered. Monitoring can be used to evaluate theneed for further treatment with the same MS therapy, or for additionalMS treatment. Generally, a decrease in one or more of the parametersdescribed above is indicative of the improved condition of the subject.

In certain embodiment, responsive to a determination of the value of thecomposite parameter and/or monitoring, the method further includes oneor more of:

(1) stratifying a patient population (e.g., assigning a subject, e.g., apatient, to a group or class);

(2) identifying or selecting the subject as likely or unlikely torespond to a treatment;

(3) selecting a treatment option, e.g., administering or notadministering an MS therapy; or

(4) prognosticating the time course of the disease in the subject (e.g.,evaluating the likelihood of increased or decreased patient survival).

Systems

In another aspect, the invention features a system for evaluating asubject (e.g., a patient, a patient group or a patient population). Thesystem includes at least one processor operatively connected to amemory, the at least one processor when executing is configured to:

determine or calculate a value of a composite parameter associated withthe subject, wherein the processor is further configured to calculatethe value of the composite parameter responsive to establishing anattention factor for the subject and a memory factor for the subject;and

evaluate the subject, based on at least one value of the compositeparameter established, e.g., prior to, during, or after the conclusionof, an MS therapy, or established responsive to administration of an MStherapy.

In a related aspect, the invention features a system for monitoring asubject (e.g., monitoring disease progression in the subject), havingmultiple sclerosis (MS), or at risk for developing MS, comprising:

at least one processor operatively connected to a memory, the at leastone processor when executing is configured to:

establish a value of a composite parameter associated with the subject,prior to, during, and/or after an MS therapy, wherein the processor isfurther configured to establish the value of the composite parameterresponsive to establishing an attention factor for the subject and amemory factor for the subject;

compare the value of the composite parameter from the subject to areference value,

(optionally) establish a reference value reflective of a severity of MSassociated with the subject, and

identify an indication of improved cognitive function in the subject inresponse to MS therapy, wherein identifying the indication of improvedcognitive function includes detecting an increase in the value of thecomposite parameter, relative to the reference value; or

identify an indication of decreased cognitive function in the subject inresponse to MS therapy, wherein identifying the indication of decreasedcognitive function includes detecting a decrease in the value of thecomposite parameter, relative to the reference value.

In certain embodiments of the systems as described herein, the processorwhen executing is further configured to perform one or more of:

comparing the value of the composite parameter from the subject to aspecified parameter, e.g., a reference value as described herein;

identifying the subject as being in need of an MS therapy;

recommending administration of an MS therapy;

determining or altering a dosing of the MS therapy;

determining or altering a schedule or a time course of the MS therapy;or

recommending an alternative MS therapy.

In one embodiment of the systems as described herein, the processor whenexecuting is further configured to establish the reference value with ahigher value for a patient having relapse remitting multiple sclerosis(RRMS) when compared to a reference value for a patient with secondaryprogressive multiple sclerosis (SPMS).

In another embodiment, the processor when executing is furtherconfigured to identify an indication of improved cognitive function inthe subject, wherein identifying the indication of improved cognitivefunction includes detecting an increase in the value of the compositeparameter, relative to the reference value.

In yet another embodiment, the processor when executing is furtherconfigured to identify an indication of decreased cognitive function inthe subject, wherein identifying the indication of decreased cognitivefunction includes detecting a decrease in the value of the compositeparameter, relative to the reference value.

The reference value can be adjusted based at least in part on the timingof establishing a first composite value and at least one subsequentcomposite value.

In yet other embodiments of the system, the processor when executing isfurther configured to determine the value of the composite parameterbased on evaluation of a plurality of attention and memory factors,e.g., one, two, three, four or more attention and memory factors.

In other embodiments of the system, the processor when executing isfurther configured to establish the memory factor from one or moreverbal or visual memory factors.

In other embodiments of the system, the processor when executing isconfigured to determine the attention and memory factors, at least inpart, from administering, or on the results from administration, of one,two, three, four or more of:

(i) an assessment of processes involved in learning and/or rememberingvisual information (e.g., Selective Reminding Test (SRT)),

(ii) an assessment of visuospatial memory (e.g., Brief VisuospatialMemory Test (BVMT)),

(iii) an assessment of complex scanning and/or visual tracking (e.g.,Symbol Digit Modalities Test (SDMT), or

(iv) an assessment of one or more of auditory information processingspeed, flexibility or calculation ability (e.g., Paced Auditory SerialAddition Test (PASAT)). In one embodiment, the assessment includes averbal instruction. In other embodiments, the assessment is supplied byan electronic means, e.g., a tablet; the electronic means can be used tocapture the response.

In yet other embodiments of the system, the processor when executing isfurther configured to establish the reference value from one or morevalues obtained from testing of at least one of: a healthy subject or anaverage of healthy subjects; the subject at different time intervals(e.g., prior to, during, or after the MS therapy); a group of MSpatients having the same or different disease progressions; the group ofMS patients having the same or different disease progressions atdifferent time intervals; a group of MS patients undergoing different MStreatments than the subject; or a group of MS patients undergoing a sameMS treatment as the subject.

In other embodiments of the system, the processor when executing isfurther configured to compute an average value of one or more memoryfactors and one or more attention factors to determine the value of thecomposite parameter.

In other embodiments of the system, the processor when executing isfurther configured to compute an average value of the sum of anassessment of complex scanning and/or visual tracking and the average ofat least two assessments of auditory information processing speed,flexibility or calculation ability.

In other embodiments of the system, the processor when executing isfurther configured to compute the value of the attention factor based ondetermining a value for the equation (SMDT+[PASAT 3+PASAT 2]/2))/2.

In other embodiments of the system, the one or more memory factorsinclude a verbal memory factor, and wherein the processor when executingis further configured to compute the value of the verbal memory factorbased on the average of the sum of at least two assessments of processesinvolved in learning and/or remembering visual information.

In other embodiments of the system, the one or more memory factorsinclude a verbal memory factor, and wherein the processor when executingis further configured to compute the value of the verbal memory factorbased on determining a value for the equation (SRT Total Learning+SRTDelayed Recall)/2.

In other embodiments of the system, the one or more memory factorsinclude a visual memory factor, and wherein the processor when executingis further configured to compute the value of the visual memory factorbased on an average of at least two assessments of visuospatial memory.

In other embodiments of the system, the one or more memory factorsinclude a visual memory factor, and wherein the processor when executingis further configured to compute the value of the visual memory factorbased on determining a value for the equation (BVMT Total Recall+BVMTDelayed Recall)/2.

In yet other embodiments of the system, the one or more memory factorsinclude a visual memory factor and a verbal memory factor, wherein theprocessor when executing is further configured to compute the value ofthe one or more memory factors from the average of the value of theverbal memory factor and the visual memory factor.

In other embodiments of the system, the processor when executing isfurther configured to:

compute a reliability value for the composite parameter, and

evaluate the reliability value against a minimum threshold parameterincluding at least one of the threshold parameter set for at least 0.65,0.69, 0.70, 0.75, 0.80, 0.85 or higher.

In other embodiments of the system, the processor when executing isfurther configured to perform one or more of the following responsive toa determination or comparison of the value of the composite parameter:

(1) stratify a patient population, wherein stratifying the patientpopulation includes at least one of assigning a subject to a group orclass having a common diagnostic characteristic;

(2) identify or select the subject as likely or unlikely to respond to atreatment;

(3) select a treatment option, including a determination to administeror not administer a preselected MS therapy; or

(4) generate a probabilistic model of the time course of the disease inthe subject, including a determination of the likelihood of increased ordecreased patient survival.

In other embodiments of the system, the processor when executing isfurther configured to:

store the value of the composite parameter, and

generate a report including analysis of the stored composite value,wherein the analysis is reflective of a status of the subject having MS.

In other embodiments of the system, the processor when executing isfurther configured to communicate information regarding a patientpopulation including a plurality of the composite parametercorresponding to a plurality of subjects.

In other embodiments of the system, the processor when executing isfurther configured to communicate information regarding an evaluation ofa subject or treatment to a report-receiving party or entity (e.g., apatient, a health care provider, a diagnostic provider, and/or aregulatory agency, e.g., the FDA).

In other embodiments of the system, the processor when executing isfurther configured to:

store a value of a composite parameter comprising an attention factorand memory factor, in a subject having multiple sclerosis (MS), or atrisk for developing MS, prior to, during, and/or after the MS therapy;and

generate a correlation between the stored composite parameter anddiagnosis of a status of the subject having MS;

communicate the correlation and the diagnosis to at least one of ahealth care provider, a diagnostic provider, and a regulatory agency.

In another aspect, the invention features system for evaluating and/orquantifying cognitive function, or evaluating disease progression, in asubject having MS, or at risk of developing MS. The system includes atleast one processor operatively connected to a memory configured to:

establish a value of a composite parameter associated with the subjectindicative of cognitive function, wherein the at least one processor isfurther configured to establish the value of the composite parameterresponsive to establishing a first value for an attention and/orprocessing speed (PS) factor and a second value for a memory factor,wherein the at least one processor when executing is configured to:

compute an average value of scores from at least two assessmentsindicative of attention and/or processing speed to determine the firstvalue, and

compute an average value of scores from at least one assessment ofauditory/verbal learning and memory, and a score from at least oneassessment of visual learning and memory to determine the second value;

compute the value of the composite parameter from a combination of thefirst and second values;

(optionally) compare the value of the composite parameter from thesubject to a reference value, and

identify an indication of improved cognitive function in the subject,wherein identifying the indication of improved cognitive functionincludes detecting an increase in the value of the composite parameter,relative to a reference value; or

identify an indication of decreased cognitive function in the subject,wherein identifying the indication of decreased cognitive functionincludes detecting a decrease in the value of the composite parameter,relative to the reference value.

In another aspect, the invention features a computer implemented methodfor evaluating and/or quantifying cognitive function, or evaluatingdisease progression, in a subject having MS, or at risk for developingMS. The method comprises:

establishing, by a computer system, a value of a composite parameterassociated with the subject indicative of cognitive function, whereinestablishing the value of the composite parameter includes establishinga first value for an attention and/or processing speed (PS) factor and asecond value for a memory factor,

computing, by a computer system, an average value of scores from atleast two assessments indicative of attention and/or processing speed todetermine the first value, and

computing, by a computer system, an average value of scores from atleast one assessment of auditory/verbal learning and memory, and a scorefrom at least one assessment of visual learning and memory to determinethe second value;

computing, by a computer system, the value of the composite parameterfrom a combination of the first and second values;

(optionally) comparing, by the computer system, the value of thecomposite parameter from the subject to a reference value, and

identifying, by the computer system, an indication of improved cognitivefunction in the subject, wherein identifying the indication of improvedcognitive function includes detecting an increase in the value of thecomposite parameter, relative to a reference value; or

identifying, by the computer system, an indication of decreasedcognitive function in the subject, wherein identifying the indication ofdecreased cognitive function includes detecting a decrease in the valueof the composite parameter, relative to the reference value.

Further embodiments of the system and computer-implemented methodsinclude one or more of the following:

In certain embodiment, at least one processor of the system isconfigured to determine, or the method establishes, at least a portionof the first value by performing one or more of:

(i) compute an average value of the scores from at least one assessmentof complex scanning and/or visual tracking, and the average value fromat least one or two assessment(s) of processing speed, flexibilityand/or calculation ability;

(ii) compute a function of a score based on a Symbol Digit ModalitiesTest (SMDT)) and a function of a score based on at least one or twoPaced Auditory Serial Addition Test (PASAT); or

(iii) compute the first value based on determining a value for theequation ((Symbol Digit Modalities Test (SDMT) score+(a first PacedAuditory Serial Addition Test (“PASAT”) score (e.g., PASAT 3″) and asecond PASAT score (e.g., PASAT 2″))/2)/2.

In other embodiments, at least one processor of the system is configuredto determine, or the method establishes, at least a portion of thesecond value by performing one or more of:

(i) compute an average value of the scores from at least one or twoassessments indicative of verbal learning and delayed recall, and theaverage value of at least one or two assessments indicative of visuallearning and delayed recall;

(ii) compute an average value of the scores from at least one or twocomponents of a Selective Reminding Test (SRT) and at least one or twocomponents of a Brief Visuospatial memory Test (BVMT); or

(iii) compute the second value based on determining a value for theequation: [SRT learning score+SRT delay score+BVMT learning score andBVMT delay score]/4.

In certain embodiments, at least one processor of the system is furtherconfigured to compute, or the method establishes, a reliability valuefor the composite parameter, and evaluate the reliability value againsta minimum threshold parameter including at least one of the thresholdparameter set for at least 0.65, 0.69, 0.70, 0.75, 0.80, 0.85 or higher.

At least one processor of the system when executing can be furtherconfigured to, or the method includes a step to, weigh equally the firstand the second values, or configured to weigh differentially (e.g., saidfirst or second value being about 10%, 20%, 25%, 30%, 40%, 60%, 75% ormore the value of the other value).

In other embodiments, the at least one processor of the system whenexecuting is further configured to, or the method includes a step to,weigh equally or differentially (e.g., as described herein) the scoresfrom the assessments used to obtain the second value.

In yet other embodiments, the at least one processor of the system whenexecuting is further configured to, or the method includes a step to,weigh equally or differentially (e.g., as described herein) the scoresfrom the assessments of verbal and visual memory. The system can befurther configured to weigh equally or differentially the scores fromthe assessments of learning and delayed recall components.

In other embodiments, the at least one processor of the system whenexecuting is further configured to, or the method includes a step to,weigh equally or differentially the scores from the at least oneassessment of complex scanning and/or visual tracking, and the scoresfrom the at least one or two assessment(s) of processing speed,flexibility and/or calculation ability.

In certain embodiments, the at least one processor of the system isconfigured to, or the method includes a step to, evaluate the compositeparameter against a probabilistic model of a time course progression ofdisease effect on cognition for the subject, wherein the probabilisticmodel includes the reference value.

In other embodiments, the at least one processor of the system isconfigured to, or the method includes a step to, generate theprobabilistic model of the time course progression of the disease effecton cognition for the subject including a time course of the referencevalue.

In one embodiment, the at least one processor of the system isconfigured to, or the method includes a step to, generate theprobabilistic model from at least one or more of: a healthy subject; agroup of healthy subjects; the subject prior to, during, or after the MStherapy; a group of MS patients having the same disease progressions; agroup of MS patients having different disease progressions; a group ofMS patients having the same or different disease progressions atdifferent time intervals; a group of MS patients undergoing different MStreatments than the subject; or a group of MS patients undergoing a sameMS treatment as the subject.

In another embodiment, the at least one processor of the system isconfigured to, or the method includes a step to, identify patientshaving similar MS disease progression from a model population.

In other embodiments, the at least one processor of the system isconfigured to, or the method includes a step to:

compute a SRT Total Learning value, SRT Delayed Recall value, BVMT TotalRecall value, BVMT Delayed Recall value to establish a memory factorportion for the reference value;

compute a SDMT value, a first PASAT, a second PASAT value to establishan attention factor portion; and

compute a combination of the memory factor portion and the attentionfactor portion to obtain the reference value.

In other embodiments, the at least one processor of the system whenexecuting is further configured to, or the method includes a step to,perform one or more of:

comparing the value of the composite parameter from the subject to areference value for a time parameter defined for a course of MSprogression;

identifying the subject as being in need of an MS therapy;

recommending administration of an MS therapy;

determining or altering a dosing of the MS therapy;

determining or altering a schedule or a time course of the MS therapy;and

recommending an alternative MS therapy.

In other embodiments, the at least one processor of the system whenexecuting is further configured to, or the method includes a step to:

capture a plurality of values of the composite parameter for the subjectover time, and

generate a model of the time course progression of the compositeparameter, wherein the model is reflective of a disease state of thesubject having MS.

Kits

In another aspect, the invention features kits for acquiring a value ofthe composite parameter for a subject, e.g., an MS patient. The kit caninclude means or tests for evaluating one, two, three, four or moreattention and memory factors described herein. In certain embodiments,the kit includes one, two, three, four or more of:

(i) an assessment of processes involved in learning and/or rememberingvisual information (e.g., Selective Reminding Test (SRT)),

(ii) an assessment of visuospatial memory (e.g., Brief Visual/spatialMemory Test (BVMT)),

(iii) an assessment of complex scanning and/or visual tracking (e.g.,Symbol Digit Modalities Test (SDMT), or

(iv) an assessment of one or more of auditory information processingspeed, flexibility or calculation ability (e.g., Paced Auditory SerialAddition Test (PASAT));

and means for determining the value of the composite parameter, e.g., avalue of a composite parameter associated with the subject, prior to,during, and/or after an MS therapy.

Reports

The methods, systems, and/or kits described herein can further includeproviding or generating, and/or transmitting information, e.g., areport, containing data of the evaluation or treatment determined by themethods, and/or kits as described herein. In one embodiment, the valueof the composite parameter is memorialized. The value or information canbe transmitted to a report-receiving party or entity (e.g., a patient, ahealth care provider, a diagnostic provider, and/or a regulatory agency,e.g., the FDA), or otherwise submitting information about the methodsand kits disclosed herein to another party. The method can relate tocompliance with a regulatory requirement, e.g., a pre- or post approvalrequirement of a regulatory agency, e.g., the FDA. In one embodiment,the report-receiving party or entity can determine if a predeterminedrequirement or reference value is met by the data, and, optionally, aresponse from the report-receiving entity or party is received, e.g., bya physician, patient, diagnostic provider.

In other embodiments, a method for generating a report, includesacquiring a value of a composite parameter comprising an attentionfactor and memory factor, in a subject (e.g., a patient, a patient groupor a patient population), having multiple sclerosis (MS), or at risk fordeveloping MS, prior to, during, and/or after the MS therapy; andmemorializing the value acquired.

In one aspect, the invention features a method for generating a report,comprising: acquiring a value of a composite parameter comprising anattention factor and memory factor, in a subject having multiplesclerosis (MS), or at risk for developing MS, prior to, during, and/orafter the MS therapy; and memorializing the value in the report.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the present invention, suitable methods andmaterials are described below. All publications, patent applications,patents, and other references mentioned herein are incorporated byreference in their entirety. In addition, the materials, methods, andexamples are illustrative only and not intended to be limiting.

Other features and advantages of the invention will be apparent from thedetailed description, drawings, and from the claims.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1A is a line graph depicting the effect size of PASAT in SPMSsubjects from the IMPACT trial. FIG. 1B is a line graph depicting theeffect size of PASAT in PPMS subjects from the OLYMPUS trial.

FIG. 2 is a diagram illustrating the methodology of constructing thecomposite parameter. The composite parameter is constructed by averagingthe learning and memory (LM) factor and the processing speed (PS)factor. The LM factor is the average of the standard scores of the SRTTotal Learning, SRT Delayed Recall, BVMT-R Total Learning, and BVMT-RRecall factors. The PS factor is the average of the two PASAT totalscores (i.e., PASAT 3″ and PASAT 2″) subsequently averaged with the SDMTscore.

FIG. 3 illustrates an example process 200 for determining a compositeparameter value for a subject, which can be executed on a computersystem according to some embodiments.

FIG. 4 illustrates an example process 300 that can be executed on acomputer system for defining correlations between a composite parametervalue and progression of MS or MS symptoms in a subject.

FIG. 5 shows an example block diagram of a general-purpose computersystem 400 which can be especially configured to practice variousaspects of the invention discussed herein.

FIG. 6 is a schematic of a storage device 412.

FIG. 7 shows an architecture diagram of an example distributed system600

FIG. 7 is a schematic of general-purpose computer systems 604, 606, and608 communicating over network 602.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides, at least in part, methods, systems andkits for the identification, assessment and/or treatment of a subjecthaving a neurological disorder, e.g., multiple sclerosis (MS). In oneembodiment, the methods, systems and kits include the step of detectingand/or quantifying a cognitive impairment in the subject (e.g., an MSpatient), by obtaining a composite cognitive endpoint that includes ameasure of processing speed and a measure of learning and memory(referred to herein as an “attention factor” and a “memory factor,”respectively).

Composite cognitive endpoints offer several advantages over currentmethodologies, including, but not limited to, increased sensitivity,enhanced statistical power, smaller sampling size and enhancedsimplicity. The invention can, therefore, be used, for example, for oneor more of: (i) diagnosing, prognosing and/or evaluating, a subject(e.g., an MS patient); (ii) evaluating responsiveness to, or monitoring,a therapy (e.g., an MS therapy); (iii) identifying a patient as beingstable, or showing an improvement or disease progression; (iv) tostratify a subject (e.g., an MS patient or patient population) as beinga disease non-progressor or a disease progressor; and/or (v) moreeffectively monitoring, treating multiple sclerosis, or preventingworsening of disease and/or relapse.

Various aspects of the invention are described in further detail in thefollowing subsections.

DEFINITIONS

As used herein, each of the following terms has the meaning associatedwith it in this section.

As used herein, the articles “a” and “an” refer to one or to more thanone (e.g., to at least one) of the grammatical object of the article.

The term “or” is used herein to mean, and is used interchangeably with,the term “and/or”, unless context clearly indicates otherwise.

“Acquire” or “acquiring” as the terms are used herein, refer toobtaining possession of, determining, or evaluating, a value, e.g., anumerical value, by “directly acquiring” or “indirectly acquiring” thevalue. “Directly acquiring” means performing a process (e.g., performinga test, e.g., a cognitive test) to obtain the value. “Indirectlyacquiring” refers to receiving the value from another party or source(e.g., a third party clinician or health professional that directlyacquired the value).

A “composite parameter” as used herein in the context of cognitiveendpoints refers to an integration of pre-selected measures of cognitivefunction (including, e.g., a measure of processing speed and a measureof learning and memory) into a consolidated index(es) or value(s). Inthe context of MS, the value of the composite parameter can beindicative of cognitive function in a domain including one or more of:information processing speed, information processing efficiency, visualmemory, verbal memory (e.g., memory acquisition), executive function orperceptual processing. In certain embodiments, the composite parameterused is an average value of one or more memory factors and one or moreattention factors.

Multiple sclerosis is “treated,” “inhibited” or “reduced,” if at leastone symptom of the disease is reduced, alleviated, terminated, slowed,or prevented. As used herein, multiple sclerosis is also “treated,”“inhibited,” or “reduced,” if recurrence or relapse of the disease isreduced, slowed, delayed, or prevented. Exemplary clinical symptoms ofmultiple sclerosis that can be used to aid in determining the diseasestatus in a subject can include e.g., tingling, numbness, muscleweakness, loss of balance, blurred or double vision, slurred speech,sudden onset paralysis, lack of coordination, cognitive difficulties,fatigue, heat sensitivity, spasticity, dizziness, tremors, gaitabnormalities, speech/swallowing difficulties, and extent of lesionsassessed by imaging techniques, e.g., MRI. Clinical symptoms of MS areroutinely classified and standardized, e.g., using an EDSS ratingsystem. Typically, a decrease of one full step indicates an effective MStreatment (Kurtzke, Ann. Neurol. 36:573-79, 1994), while an increase ofone full step will indicate the progression or worsening of the disease(e.g., exacerbation).

As used herein, the “Expanded Disability Status Scale” or “EDSS” isintended to have its customary meaning in the medical practice. EDSS isa rating system that is frequently used for classifying andstandardizing MS. The accepted scores range from 0 (normal) to 10 (deathdue to MS). Typically patients having an EDSS score of about 6 will havemoderate disability (e.g., walk with a cane), whereas patients having anEDSS score of about 7 or 8 will have severe disability (e.g., willrequire a wheelchair). More specifically, EDSS scores in the range of1-3 refer to an MS patient who is fully ambulatory, but has some signsin one or more functional systems; EDSS scores in the range higher than3 to 4.5 show moderate to relatively severe disability; an EDSS score of5 to 5.5 refers to a disability impairing or precluding full dailyactivities; EDSS scores of 6 to 6.5 refer to an MS patient requiringintermittent to constant, or unilateral to bilateral constant assistance(cane, crutch or brace) to walk; EDSS scores of 7 to 7.5 means that theMS patient is unable to walk beyond five meters even with aid, and isessentially restricted to a wheelchair; EDSS scores of 8 to 8.5 refer topatients that are restricted to bed; and EDSS scores of 9 to 10 meanthat the MS patient is confined to bed, and progressively is unable tocommunicate effectively or eat and swallow, until death due to MS.

“Responsiveness,” to “respond” to treatment, and other forms of thisverb, as used herein, refer to the reaction of a subject to treatment,e.g., an MS therapy (e.g., an MS therapy as described herein). As anexample, a subject responds to treatment with the MS therapy, if atleast one symptom of multiple sclerosis (e.g., cognitive (e.g., value ofthe composite parameter) or relapse rate) in the subject is improved,reduced or retarded by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%or more. For example, a value of at least 0.2, 0.3, 0.4, 0.5, 0.6, 0.7,0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, or 1.5 SD, greater than, or lowerthan, a specified parameter indicates that the subject has increased ordecreased cognitive function, respectively, thus indicating that thesubject is more or less responsive to the treatment, respectively. Inanother example, a subject responds to MS therapy, if at least onesymptom of multiple sclerosis in the subject is reduced by about 5%,10%, 20%, 30%, 40%, 50% or more as determined by any appropriatemeasure, e.g., Expanded Disability Status Scale (EDSS) or determiningthe extent of other symptoms such as relapse rate, muscle weakness,tingling, and numbness. In another example, a subject responds to MStherapy, if the subject experiences a life expectancy extended by about5%, 10%, 20%, 30%, 40%, 50% or more beyond the life expectancy predictedif no treatment is administered. Several methods can be used todetermine if a patient responds to a treatment including the cognitive(e.g., value of the composite parameter described herein) and/or EDSScriteria, as set forth above.

A “responder” or “non-progressor” refers to a subject, e.g., an MSpatient, if in response to an MS therapy (e.g., an MS therapy describedherein), at least one symptom of multiple sclerosis (e.g., cognitiveimpairment and/or physical) in the subject is reduced by about 5%, 10%,20%, 30%, 40%, 50% or more as determined by any appropriate measure,e.g., a composite of cognitive test instruments, EDSS and/or determiningthe extent of other symptoms such as relapse rate, muscle weakness,tingling, and numbness. In one embodiment, a responder or non-progressoris defined as a subject with no confirmed relapses and no evidence ofsustained disability progression (by EDSS) during the first three yearsof treatment (e.g., clinical remission).

A “non-responder” or “progressor” refers to a subject, e.g., an MSpatient, if in response to an MS therapy (e.g., an MS therapy describedherein), at least one symptom of multiple sclerosis (e.g., cognitiveimpairment and/or physical) in the subject is reduced by less than about5%, as determined by any appropriate measure, e.g., a composite ofcognitive test instruments, EDSS and/or determining the extent of othersymptoms such as relapse rate, muscle weakness, tingling, and numbness.In one embodiment, a non-responder or progressor is defined as thosesubjects that have active disease on therapy including subjects with atleast 3 relapses, development of a 6-month sustained progression indisability defined as a 1.0 point increase in EDSS score from baselinein subjects with a baseline score of ≦5.5.

The cognitive composite score can be used to identify confirmedprogressors and confirmed non-progressors. For this, the MS subject cantake the test on at least 2 different occasions at least 1 month apart.Subject who have improvement by at least 0.25, 0.5 SD on the twooccasions can be identified as a responder. A subject who does not haveimprovement of at least 0.25, 0.5 SD can be identified as anon-responder.

As used herein, “significant event” shall refer to an event in apatient's disease that is important as determined by one skilled in theart. Examples of significant events include, for example, withoutlimitation, primary diagnosis, death, recurrence, remission, relapse ofa patient's disease or the progression of a patient's disease from anyone of the above noted stages to another. A significant event can be anyimportant event used determine disease status using e.g., EDSS or othersymptom criteria, as determined by one skilled in the art.

As used herein, “time course” shall refer to the amount of time betweenan initial event and a subsequent event. For example, with respect to apatient's disease, time course can relate to a patient's disease and canbe measured by gauging significant events in the course of the disease,wherein the first event can be diagnosis and the subsequent event can beremission or relapse, for example.

Various aspects of the invention are described in further detail below.Additional definitions are set out throughout the specification.

Cognitive Test Instruments

Several cognitive test instruments can be used to determine the value ofthe composite parameter, as follows.

Symbol Digit Modalities Test (SDMT)

The SDMT is a test that evaluates processing speed and working memory inwhich the subject is given 90 seconds to pair specific numbers withgiven geometric figures based on a reference key. It is modeled afterthe Digit Symbol or Coding Tasks tests, which have been included in theWechsler intelligence scales for many years (e.g., Wechsler et al.(1974) Manual for the Wechsler Intelligence Scale for Children—Revised.New York: Psychological Corporation; Wechsler et al. (1981) WAIS-RManual. New York: Psychological Corporation). Recognizing thelimitations some patients have with manual dexterity, Rao and colleaguesmodified the SDMT to include only an oral response (Rao et al. (1991)Neurology 41: 685-691). In this oral SDMT selected in the presentinvention, participants are presented with an 8.5×11 inch sheet thatcontains the numbers and symbols to be processed. The top row of stimuliincludes nine symbols, each of which is paired with a single digit inthe key. The remainder of the page has a pseudo-randomized sequence ofthese symbols, and the participant's task is to respond orally with thedigit associated with each of the symbols as quickly as possible. Thescore is the total number of correct matches (out of 110) made by thesubject within the 90 second time frame.

Good test-retest reliability (r=0.93-0.97, p<0.001) has been establishedin MS subjects (Benedict et al. (2006) Journal of the InternationalNeuropsychological Society 12: 549-558; Benedict et al. (2008) MultipleSclerosis 14: 940-946). Good discriminative validity for distinguishingbetween MS patients and normal controls (d=1.0-1.5, p<0.001) (see e.g.,Deloire et al. (2005) Journal of Neurology, Neurosurgery & Psychiatry76: 519-526; Benedict et al. (2006) Journal of the InternationalNeuropsychological Society 12: 549-558; Houtchens et al. (2007)Neurology 69: 113-123; Strober et al. (2009) Multiple Sclerosis 15:1077-1084; Parmenter et al. (2010) J Int Neuropsychol Soc 16: 6-16) andfor distinguishing between RRMS and SPMS patients (d=0.8, p<0.001) (seeBenedict et al. (2006) Archives of Neurology 63: 1301-1306) has alsobeen confirmed. In addition, correlations between performance and brainMRI have also been documented (see e.g., Benedict et al. (2007) MultipleSclerosis 13: 722-730; Houtchens et al. (2007) Neurology 69: 113-123;Tekok-Kilic et al. (2007) Neuro Image 36: 1294-1300).

Paced Serial Addition Test (PASAT)

First developed by Gronwall et al. to assess patients recovering fromconcussion, the PASAT requires patients to monitor a series of 61audiotaped digits while adding each consecutive digit to the oneimmediately preceding it (Gronwall et al. (1977) Perceptual and MotorSkills 44: 367-373). The PASAT requires both rapid informationprocessing and simultaneous allocation of attention to two tasks, aswell as reasonably intact calculation ability. In its original format,the PASAT was administered at four inter-stimulus intervals (2.4seconds, 2.0 seconds, 1.6 seconds, and 1.2 seconds). The number ofinter-stimulus intervals and presentation rates were subsequentlymodified by Rao and colleagues for use with MS patients to 3.0 secondsand 2.0 seconds (Rao et al. (1991) A Manual for the Brief, RepeatableBattery of Neuropsychological Tests in Multiple Sclerosis: NationalMultiple Sclerosis Society; Rao et al. (1991) NeuropsychologicalScreening Battery for Multiple Sclerosis: National Multiple SclerosisSociety; Rao et al. (1991) Neurology 41: 685-691; Rao et al. (1991)Neurology 41: 692-696).

This latter version of the test was selected to be a component of the MSFunctional Composite and the MACFIMS battery (Benedict et al. (2002)Clinical Neuropsychologist 16: 381-397). Test-retest reliability in MSpopulations ranges from r=0.78 to 0.93 (Benedict et al. (2006) Journalof the International Neuropsychological Society 16: 228-237; Drake etal. (2010) Multiple Sclerosis 16: 228-237). Good discriminative validityfor distinguishing between MS patients and normal controls (d=0.5-0.7,p<0.001 to 0.34) (Deloire et al. (2005) Journal of Neurology,Neurosurgery & Psychiatry 76: 519-526; Benedict et al. (2006) Journal ofthe International Neuropsychological Society 12: 549-558; Houtchens etal. (2007) Neurology 69: 113-123; Strober et al. (2009) MultipleSclerosis 15: 1077-1084; Parmenter et al. (2010) J Int Neuropsychol Soc16: 6-16; Drake et al. (2010) Multiple Sclerosis 16: 228-237) and fordistinguishing between RRMS and SPMS patients (d=0.5, p<0.002) (Benedictet al. (2006) Archives of Neurology 63: 1301-1306) has been confirmed.The PASAT score of interest is the total number of correct responses ateach presentation rate. Two alternate forms of the Rao version of thePASAT are available (PASAT 3″ and PASAT 2″) and were selected in thecurrent invention. In the PASAT 3″, the stimulus is presented every 3seconds, where as in the PASAT 2″, the stimulus is presented every 2seconds.

Selective Reminding Test (SRT)

The SRT was first developed by Buschke et al. (see Buschke et al. (1974)Neurology 24: 1019-1025) who conducted research in the area ofanterograde amnesia. Rather than ask patients to recall an entire wordlist on each successive learning trial, the experimenter only repeatedwords not recalled on each successive learning trial. Subsequently,several memory investigators developed normative data for the test, andalternate forms. Note, the original versions were based on a form of thetest using 15 words and 12 learning trials. Such an administration isarduous and time consuming, and therefore there has been much interestin shorter forms of the SRT. The administration procedure widely used inMS research is a six-trial form developed by Rao et al. (see e.g., Raoet al. (1991) A Manual for the Brief, Repeatable Battery ofNeuropsychological Tests in Multiple Sclerosis: National MultipleSclerosis Society; Rao et al. (1991) Neuropsychological ScreeningBattery for Multiple Sclerosis: National Multiple Sclerosis Society; Raoet al. (1991) Neurology 41: 685-691; Rao et al. (1991) Neurology 41:692-696). This six-trial format is utilized in the current invention. Anumber of different versions of SRT word lists exist. Hannay and Levin'sword lists for adults, test forms 1 and 3, are utilized in the currentinvention (Hannay et al. (1985) J Clin Exp Neuropsychol. 7: 251-263).Discriminative validity of the SRT has been established in severalstudies, with SRT discriminating between MS subjects and normal controlsd=0.6 to d=1.0 (see e.g., Rao et al. (1991) A Manual for the Brief,Repeatable Battery of Neuropsychological Tests in Multiple Sclerosis:National Multiple Sclerosis Society; Deloire et al. (2005) Journal ofNeurology, Neurosurgery & Psychiatry 76: 519-526; Strober et al. (2009)Multiple Sclerosis 15: 1077-1084). It has also been shown that SRTfindings correlate with ventricular enlargement as seen on brain MRI(R²=0.14; p, 0.05) (Christodoulou et al. (2003) Neurology 60:1793-1798).

Brief Visuospatial Memory Test-Revised (BVMT-R)

The BVMT-R is based on an initial effort to develop an equivalentalternate form visual memory test along the lines of the visualreproduction subtest from the Wechsler Memory Scale (Benedict et al.(1993) Neuropsychological Rehabilitation 3: 37-51; Benedict et al.(1995) Clinical Neuropsychologist 9: 11-16; Wechsler et al. (1987)Wechsler Memory Scale—Revised Manual. New York: PsychologicalCorporation). Initially, the BVMT included just a single exposure to aone-page presentation of six visual designs. The revised versionincludes three 10-second exposures to the stimulus (Benedict et al.(1997) Brief Visuospatial Memory Test—Revised: Professional Manual.Odessa, Fla.: Psychological Assessment Resources, Inc.; Benedict et al.(1996) Psychological Assessment 8: 145-153). After each exposure, thesubject is asked to reproduce the matrix using a pencil on a blank sheetof paper. There are rigid scoring criteria for accuracy and location.After a 25 minute delay, the patient is asked to reproduce theinformation again without another exposure. Finally a yes/no recognitiontask is presented. The BVMT-R has excellent reproducibility, withtest-retest reliability ranging from r=0.85 to r=0.91 (Benedict et al.(1996) Psychological Assessment 8: 145-153; Benedict et al. (2005)Journal of the International Neuropsychological Society 11: 727-736); aswell as good discriminative validity between MS and normal controlsubjects (d=0.9, p<0.) (Strober et al. (2009) Multiple Sclerosis 15:1077-1084; Parmenter et al. (2010) J Int Neuropsychol Soc 16: 6-16) andRRMS and SPMS patients (d=0.6, p<0.001) (Benedict et al. (2006) Archivesof Neurology 63: 1301-1306). Predictive validity, in the form ofcorrelation between BVMT-R performance and brain MRI findings, has alsobeen established (Stankiewicz, J. M., B. I. Glanz, et al. (2011). “BrainMRI lesion load at 1.5T and 3T versus clinical status in multiplesclerosis.” J Neuroimaging 21(2): e50-56). Further, there is extensiveresearch showing that all 6 forms of the test are of equivalentdifficulty. Variables of interest in the current invention are the TotalLearning and Delayed Recall scores.

Multiple Sclerosis and Methods of Diagnosis

Multiple sclerosis (MS) is a central nervous system disease that ischaracterized by inflammation and loss of myelin sheaths.

Patients having MS can be identified by clinical criteria establishing adiagnosis of clinically definite MS as defined by Poser et al. (1983)Ann. Neurol. 13:227. Briefly, an individual with clinically definite MShas had two attacks and clinical evidence of either two lesions orclinical evidence of one lesion and paraclinical evidence of another,separate lesion. Definite MS may also be diagnosed by evidence of twoattacks and oligoclonal bands of IgG in cerebrospinal fluid or bycombination of an attack, clinical evidence of two lesions andoligoclonal band of IgG in cerebrospinal fluid. The McDonald criteriacan also be used to diagnose MS. (McDonald et al. (2001) Recommendeddiagnostic criteria for Multiple sclerosis: guidelines from theInternational Panel on the Diagnosis of Multiple Sclerosis, Ann Neurol50:121-127). The McDonald criteria include the use of MRI evidence ofCNS impairment over time to be used in diagnosis of MS, in the absenceof multiple clinical attacks. Effective treatment of multiple sclerosismay be evaluated in several different ways. The following parameters canbe used to gauge effectiveness of treatment. Two exemplary criteriainclude: EDSS (extended disability status scale), and appearance ofexacerbations on MRI (magnetic resonance imaging).

The EDSS is a means to grade clinical impairment due to MS (Kurtzke etal. (1983) Neurology 33:1444). Eight functional systems are evaluatedfor the type and severity of neurologic impairment. Briefly, prior totreatment, patients are evaluated for impairment in the followingsystems: pyramidal, cerebella, brainstem, sensory, bowel and bladder,visual, cerebral, and other. Follow-ups are conducted at definedintervals. The scale ranges from 0 (normal) to 10 (death due to MS). Adecrease of one full step indicates an effective treatment (Kurtzke etal., (1994) Ann. Neurol. 36:573-79), while an increase of one full stepwill indicate the progression or worsening of disease (e.g.,exacerbation). Typically patients having an EDSS score of about 6 willhave moderate disability (e.g., walk with a cane), whereas patientshaving an EDSS score of about 7 or 8 will have severe disability (e.g.,will require a wheelchair).

Exacerbations are defined as the appearance of a new symptom that isattributable to MS and accompanied by an appropriate new neurologicabnormality (IFNB MS Study Group, supra). In addition, the exacerbationmust last at least 24 hours and be preceded by stability or improvementfor at least 30 days. Briefly, patients are given a standardneurological examination by clinicians. Exacerbations are either mild,moderate, or severe according to changes in a Neurological Rating Scale(Sipe et al. (1984) Neurology 34:1368). An annual exacerbation rate andproportion of exacerbation-free patients are determined.

Therapy can be deemed to be effective using a clinical measure if thereis a statistically significant difference in the rate or proportion ofexacerbation-free or relapse-free patients between the treated group andthe placebo group for either of these measurements. In addition, time tofirst exacerbation and exacerbation duration and severity may also bemeasured. A measure of effectiveness as therapy in this regard is astatistically significant difference in the time to first exacerbationor duration and severity in the treated group compared to control group.An exacerbation-free or relapse-free period of greater than one year, 18months, or 20 months is particularly noteworthy. Clinical measurementsinclude the relapse rate in one and two-year intervals, and a change inEDSS, including time to progression from baseline of 1.0 unit on theEDSS that persists for six months. On a Kaplan-Meier curve, a delay insustained progression of disability shows efficacy. Other criteriainclude a change in area and volume of T2 images on MRI, and the numberand volume of lesions determined by gadolinium enhanced images.

MRI can be used to measure active lesions using gadolinium-DTPA-enhancedimaging (McDonald et al., Ann. Neurol. 36:14, 1994) or the location andextent of lesions using T2-weighted techniques. Briefly, baseline MRIsare obtained. The same imaging plane and patient position are used foreach subsequent study. Positioning and imaging sequences can be chosento maximize lesion detection and facilitate lesion tracing. The samepositioning and imaging sequences can be used on subsequent studies. Thepresence, location and extent of MS lesions can be determined byradiologists. Areas of lesions can be outlined and summed slice by slicefor total lesion area. Three analyses may be done: evidence of newlesions, rate of appearance of active lesions, percentage change inlesion area (Paty et al., (1993) Neurology 43:665). Improvement due totherapy can be established by a statistically significant improvement inan individual patient compared to baseline or in a treated group versusa placebo group.

Exemplary symptoms associated with multiple sclerosis, which can betreated with the methods described herein or managed using symptommanagement therapies, include: optic neuritis, diplopia, nystagmus,ocular dysmetria, internuclear opthalmoplegia, movement and soundphosphenes, afferent pupillary defect, paresis, monoparesis,paraparesis, hemiparesis, quadraparesis, plegia, paraplegia, hemiplegia,tetraplegia, quadraplegia, spasticity, dysarthria, muscle atrophy,spasms, cramps, hypotonia, clonus, myoclonus, myokymia, restless legsyndrome, footdrop, dysfunctional reflexes, paraesthesia, anaesthesia,neuralgia, neuropathic and neurogenic pain, l'hermitte's, proprioceptivedysfunction, trigeminal neuralgia, ataxia, intention tremor, dysmetria,vestibular ataxia, vertigo, speech ataxia, dystonia, dysdiadochokinesia,frequent micturation, bladder spasticity, flaccid bladder,detrusor-sphincter dyssynergia, erectile dysfunction, anorgasmy,frigidity, constipation, fecal urgency, fecal incontinence, depression,cognitive dysfunction, dementia, mood swings, emotional lability,euphoria, bipolar syndrome, anxiety, aphasia, dysphasia, fatigue,uhthoffs symptom, gastroesophageal reflux, and sleeping disorders.

Each case of MS displays one of several patterns of presentation andsubsequent course. Most commonly, MS first manifests itself as a seriesof attacks followed by complete or partial remissions as symptomsmysteriously lessen, only to return later after a period of stability.This is called relapsing-remitting MS (RRMS). Primary-progressive MS(PPMS) is characterized by a gradual clinical decline with no distinctremissions, although there may be temporary plateaus or minor relieffrom symptoms. Secondary-progressive MS (SPMS) begins with arelapsing-remitting course followed by a later primary-progressivecourse. Rarely, patients may have a progressive-relapsing (PRMS) coursein which the disease takes a progressive path punctuated by acuteattacks. PPMS, SPMS, and PRMS are sometimes lumped together and calledchronic progressive MS.

A few patients experience malignant MS, defined as a swift andrelentless decline resulting in significant disability or even deathshortly after disease onset. This decline may be arrested or deceleratedby determining the likelihood of the patient to respond to a therapyearly in the therapeutic regime and switching the patient to an agentthat they have the highest likelihood of responding to.

In addition to the physical symptoms described above, MS can also beassociated with significant cognitive impairments. MS related cognitivesymptoms can include, impairments in memory, information processing,attention and concentration, abstract conceptualization, visuospatialskills, verbal fluency, learning, executive functions, (e.g., high levelprocesses, e.g., planning, prioritizing, and problem solving);difficulty reasoning or solving problems; decreased attention span; poorjudgment; and memory loss.

The methods provided herein are particularly useful for identifyingsubjects that are more likely to respond to, or are in need of, analternative therapy as described herein. In some embodiments, acomposite parameter is measured prior to the initiation of a therapy,and based solely on the composite parameter or based on the compositeparameter, alone or in combination with other factors (e.g., presence orabsence or degree of physical symptoms associated with MS); analternative therapy is recommended or administered. The methods providedherein are also particularly useful for identifying subjects that arenot in need of an alternative therapy. In some embodiments, a compositeparameter is measured prior to the initiation of a therapy, and basedsolely on the composite parameter, or based on the composite parameterin combination with other factors (e.g., presence/absence or degree ofphysical symptoms associated with MS).

The methods described herein can also be used to monitor a response to atherapy. Such methods are useful for detection of tolerance to atherapy, ineffectiveness of a therapy, or a positive response to atherapy. In some embodiments, a composite parameter is measured at least2 weeks, at least 1 month, at least 3 months, at least 6 months, or atleast 1 year after initiation of a therapy. In some embodiments, it ispreferred that a composite parameter is measured less than 6 monthsafter initiation of therapy to permit the skilled practitioner to switchthe subject to a different therapeutic strategy. Thus, in someembodiments it is preferred that a composite parameter is measuredwithin 1-6 months, 1-5 months, 1-4 months, 1-3 months, 1-2 months, 2-6months, 3-6 months, 4-6 months, 5-6 months, 2-3 months, 3-4 months, or4-5 months of initiation of therapy.

In some embodiments, the composite parameter is compared to a referencevalue or cut-off value. For example, a cut-off value can be determinedthat represents a particular therapy should be administered. In anotherexample, a cut-off value can be determined that represents anon-responder status; any values falling below the cut-off value arelikely to be non-responders to a current therapy.

In some embodiments, a change in the composite parameter is determined.In one embodiment, the change in the composite parameter is determinedby comparing the composite parameter acquired for a subject with MS attwo or more timepoints (e.g., at baseline and 3 months after initiationof therapy or 3 and 6 months after initiation of therapy).

The present invention also pertains to the field of predictive medicinein which diagnostic assays, pharmacogenomics, and monitoring clinicaltrials are used for predictive purposes to thereby treat an individualprophylactically. Accordingly, one aspect of the present inventionrelates to methods for determining a composite parameter, in order todetermine whether an individual having multiple sclerosis or at risk ofdeveloping multiple sclerosis should be administered an alternativetherapy.

In one aspect, the invention is drawn to a method for determiningwhether a subject is in need of a MS therapy. In another aspect, themethod is drawn to selecting an MS therapy. In another aspect, theinvention is drawn to a method of administering a MS therapy. In anotheraspect the, the invention is drawn to a method of altering dosing of aMS therapy. In another aspect, the invention is drawn to a method ofaltering a schedule or a time course of a MS therapy. In still anotheraspect, the invention is drawn to a method of administering analternative MS therapy.

In certain embodiments, the method comprises acquiring a value of acomposite parameter from a subject as described herein and determiningwhether the subject is in need of a MS therapy. In certain embodiments,the method comprises acquiring a value of a composite parameter from asubject as described herein and selecting; altering composition of;altering dosage of; or altering dosing schedule of; an MS therapy.

In some embodiments, the methods involve evaluation of a subject e.g., apatient, a patient group or a patient population, e.g., a patient whohas been diagnosed with or is suspected of having multiple sclerosis,e.g., presents with symptoms of multiple sclerosis, to acquire a valueof a composite parameter described herein.

In some embodiments, the results of the acquisition of the compositeparameter and the interpretation thereof, are predictive of thepatient's need for or response to treatment with an alternative therapy.According to the present invention, a composite parameter describedherein, can be indicative that treatment with an alternative therapyshould be recommended or administered.

In yet another embodiment, the composite parameter is assessed atpre-determined intervals, e.g., a first point in time and at least at asubsequent point in time. In one embodiment, a time course is measuredby determining the time between significant events in the course of apatient's disease, wherein the measurement is predictive of whether apatient has a long time course. In another embodiment, the significantevent is the progression from primary diagnosis to death. In anotherembodiment, the significant event is the progression from primarydiagnosis to worsening disease. In another embodiment, the significantevent is the progression from primary diagnosis to relapse. In anotherembodiment, the significant event is the progression from secondary MSto death. In another embodiment, the significant event is theprogression from remission to relapse. In another embodiment, thesignificant event is the progression from relapse to death. In certainembodiments, the time course is measured with respect to one or more ofoverall survival rate, time to progression and/or using the EDSS orother assessment criteria.

The methods described herein can be used in any subject having multiplesclerosis including sub-types such as benign MS, quiescentrelapsing-remitting MS, active relapsing-remitting MS, primaryprogressive MS, and secondary progressive MS. It is also contemplated,in other embodiments, that the methods can be used in subjects havingMS-like symptoms, such as those having clinically isolated syndrome(CIS) or clinically defined MS (CDMS). Clinically isolated syndrome(CIS) refers to the detection of a single clinical episode ofdemyelination or other monophasic CNS inflammatory disorder (e.g.,Spinal Cord Syndrome, Brainstem/Cerebellar Syndrome, and othersdescribed below). Frohman et al. (2003) Neurology 2003 61(5):602-1 1report that, in subjects with CIS, three or more white matter lesions ona T2-weighted MRI scan (especially if one of these lesions is located inthe periventricular region) is a very sensitive predictor (>80%) of thesubsequent development of CDMS within the next 7 to 10 years. In apreferred embodiment, the methods described herein are used to assessexpression of one or more biomarkers of Table 1 in a subject havingRRMS.

In an aspect of the invention, the method is drawn to the evaluation ofpharmaceutical agents for their effectiveness for treating MS. In someembodiments, the composite parameter is used as a measure of theeffectiveness of a pharmaceutical agent for treating MS. In someembodiments, the change in the composite parameter assessed atpre-determined intervals, e.g., a first point in time and at least at asubsequent point in time, is used as a measure of the effectiveness of apharmaceutical agent for treating MS.

MS Therapeutic Agents, Compositions and Administration

There are several medications presently used to modify the course ofmultiple sclerosis in patients. Such agents include, but are not limitedto, Beta interferons (e.g., Avonex®, Rebif®, Betaseron®, Betaferon®etc.)), glatiramer (Copaxone®), natalizumab (Tysabri®), and mitoxantrone(Novantrone®).

IFNβ Agents (Beta Interferons)

One known therapy for MS includes treatment with interferon beta.Interferons (IFNs) are natural proteins produced by the cells of theimmune systems of most animals in response to challenges by foreignagents such as viruses, bacteria, parasites and tumor cells. Interferonsbelong to the large class of glycoproteins known as cytokines.Interferon beta has 165 amino acids. Interferons alpha and beta areproduced by many cell types, including T-cells and B-cells, macrophages,fibroblasts, endothelial cells, osteoblasts and others, and stimulateboth macrophages and NK cells. Interferon gamma is involved in theregulation of immune and inflammatory responses. It is produced byactivated T-cells and Th1 cells.

Several different types of interferon are now approved for use inhumans. Interferon alpha (including forms interferon alpha-2a,interferon alpha-2b, and interferon alfacon-1) was approved by theUnited States Food and Drug Administration (FDA) as a treatment forHepatitis C. There are two currently FDA-approved types of interferonbeta. Interferon beta 1a (Avonex®) is identical to interferon beta foundnaturally in humans, and interferon beta 1b (Betaseron®) differs incertain ways from interferon beta 1a found naturally in humans,including that it contains a serine residue in place of a cysteineresidue at position 17. Other uses of interferon beta have includedtreatment of AIDS, cutaneous T-cell lymphoma, Acute Hepatitis C (non-A,non-B), Kaposi's sarcoma, malignant melanoma, and metastatic renal cellcarcinoma.

IFNβ agents can be administered to the subject by any method known inthe art, including systemically (e.g., orally, parenterally,subcutaneously, intravenously, rectally, intramuscularly,intraperitoneally, intranasally, transdermally, or by inhalation orintracavitary installation). Typically, the IFNβ agents are administeredsubcutaneously, or intramuscularly.

IFNβ agents can be used to treat those subjects determined to be“responders” using the methods described herein. In one embodiment, theIFNβ agents are used as a monotherapy (i.e., as a single “diseasemodifying therapy”) although the treatment regimen can further comprisethe use of “symptom management therapies” such as antidepressants,analgesics, anti-tremor agents, etc. In one embodiment, the IFNβ agentis an IFNβ-1A agent (e.g., Avonex®, Rebif®). In another embodiment, theINFβ agent is an INFβ-1B agent (e.g., Betaseron®, Betaferon®).

Avonex®, an Interferon β-1a, is indicated for the treatment of patientswith relapsing forms of MS that are determined to be responders usingthe methods described herein to slow the accumulation of physicaldisability and decrease the frequency of clinical exacerbations. Avonex®(Interferon beta-1a) is a 166 amino acid glycoprotein with a predictedmolecular weight of approximately 22,500 daltons. It is produced byrecombinant DNA technology using genetically engineered Chinese HamsterOvary cells into which the human interferon beta gene has beenintroduced. The amino acid sequence of Avonex® is identical to that ofnatural human interferon beta. The recommended dosage of Avonex®(Interferon beta-1a) is 30 mcg injected intramuscularly once a week.Avonex® is commercially available as a 30 mcg lyophilized powder vial oras a 30 mcg prefilled syringe.

Interferon beta Ia (Avonex®) is identical to interferon beta foundnaturally in humans (AVONEX®, i.e., Interferon beta Ia (SwissProtAccession No. P01574 and gi:50593016). The sequence of interferon betais:

(SEQ ID NO: 1) MTNKCLLQIALLLCFSTTALSMSYNLLGFLQRSSNFQCQKLLWQLNGRLEYCLKDRMNFDIPEEIKQLQQFQKEDAALTIYEMLQNIFAIFRQDSSSTGWNETIVENLLANVYHQINHLKTVLEEKLEKEDFTRGKLMSSLHLKRYYGRILHYLKAKEYSHCAWTIVRVEILRNF YFINRLTGYLRN.

In one embodiment, the interferon beta molecule includes the amino acidsequence of SEQ ID NO:1, or an amino acid sequence substantiallyhomologous thereto (e.g., at least 70%, 80%, 90%, 95%, or more identicalthereto).

Methods for Making Avonex® are Known in the Art.

Treatment of responders identified using the methods described hereinfurther contemplates that compositions (e.g., IFN beta 1a molecules)having biological activity that is substantially similar to that ofAVONEX® will permit successful treatment similar to treatment withAVONEX® when administered in a similar manner. Such other compositionsinclude, e.g., other interferons and fragments, analogues, homologues,derivatives, and natural variants thereof with substantially similarbiological activity. In one embodiment, the INFβ agent is modified toincrease one or more pharmacokinetic properties. For example, the INFβagent can be a modified form of interferon 1a to include a pegylatedmoiety. PEGylated forms of interferon beta 1a are described in, e.g.,Baker, D. P. et al. (2006) Bioconjug Chem 17(1):179-88; Arduini, R M etal. (2004) Protein Expr Purif 34(2):229-42; Pepinsky, R B et al. (2001)J. Pharmacol. Exp. Ther. 297(3):1059-66; Baker, D. P. et al. (2010) JInterferon Cytokine Res 30(10):777-85 (all of which are incorporatedherein by reference in their entirety, and describe a human interferonbeta 1a modified at its N-terminal alpha amino acid to include a PEGmoiety, e.g., a 20 kDa mPEG-O-2-methylpropionaldehyde moiety). Pegylatedforms of IFN beta 1a can be administered by, e.g., injectable routes ofadministration (e.g., subcutaneously).

Rebif® is also an Interferon β-1a agent, while Betaseron® and Betaferon®are Interferon β-1b agents. Both Rebif® and Betaseron® are formulatedfor administration by subcutaneous injection.

Dosages of IFNβ agents to administer can be determined by one of skillin the art, and include clinically acceptable amounts to administerbased on the specific interferon-beta agent used. For example, AVONEX®is typically administered at 30 microgram once a week via intramuscularinjection. Other forms of interferon beta 1a, specifically REBIF®, isadministered, for example, at 22 microgram three times a week or 44micrograms once a week, via subcutaneous injection. Interferon beta-1Acan be administered, e.g., intramuscularly, in an amount of between 10and 50 μg. For example, AVONEX® can be administered every five to tendays, e.g., once a week, while Rebif® can be administered three times aweek.

Non-IFNβ Agents

In subjects determined to be non-responders using the methods describedherein, a skilled physician can select a therapy that includes anon-IFNβ agent, e.g., glatiramer (Copaxone®), natalizumab (Tysabri®,Antegren®), mitoxantrone (Novantrone®), dimethyl fumarate (BG-12®), arepatative agent; an anti-LINGO antibody, an inhibitor of adihydroorotate dehydrogenase (e.g., teriflunomide), among others.

Steroids, e.g., corticosteroid, and ACTH agents can be used to treatacute relapses in relapsing-remitting MS or secondary progressive MS.Such agents include, but are not limited to, Depo-Medrol®, Solu-Medrol®,Deltasone®, Delta-Cortef®, Medrol®, Decadron®, and Acthar®.

Natalizumab (Tysabri)

Natalizumab inhibits the migration of leukocytes from the blood to thecentral nervous system. Natalizumab binds to VLA-4 (also called α4β1) onthe surface of activated T-cells and other mononuclear leukocytes. Itcan disrupt adhesion between the T-cell and endothelial cells, and thusprevent migration of mononuclear leukocytes across the endothelium andinto the parenchyma. As a result, the levels of pro-inflammatorycytokines can also be reduced. Natalizumab can decrease the number ofbrain lesions and clinical relapses in patients with relapse remittingmultiple sclerosis and relapsing secondary-progressive multiplesclerosis.

Natalizumab and related VLA-4 binding antibodies are described, e.g., inU.S. Pat. No. 5,840,299. Monoclonal antibodies 21.6 and HP1/2 areexemplary murine monoclonal antibodies that bind VLA-4. Natalizumab is ahumanized version of murine monoclonal antibody 21.6 (see, e.g., U.S.Pat. No. 5,840,299). A humanized version of HP 1/2 has also beendescribed (see, e.g., U.S. Pat. No. 6,602,503). Several additional VLA-4binding monoclonal antibodies, such as HP2/1, HP2/4, L25 and P4C2, aredescribed, e.g., in U.S. Pat. No. 6,602,503; Sanchez-Madrid et al,(1986) Eur. J. Immunol 16:1343-1349; Hemler et al, (1987) J Biol. Chem.2:11478-11485; Issekutz et al. (1991) J Immunol 147: 109 (TA-2 mab);Pulido et al. (1991) J Biol. Chem. 266: 10241-10245; and U.S. Pat. No.5,888,507).

BG-12® (Dimethyl Fumarate)

BG-12® (dimethyl fumarate) is a fumaric acid ester. BG-12 is thought todecrease leukocyte passage through the blood brain barrier and exertneuroprotective effects by the activation of antioxidative pathways,specifically through activation of the Nrf-2 pathway (Lee et al. (2008)Int MS Journal 15: 12-18). Research also suggests that BG-12® has thepotential to reduce the activity and impact of inflammatory cells on theCNS and induce direct cytoprotective responses in CNS cells. Theseeffects may enhance the CNS cells' ability to mitigate the toxicinflammatory and oxidative stress that plays a role in MSpathophysiology.

Copaxone® (Glatiramer Acetate)

Copaxone® (glatiramer acetate) consists of the acetate salts ofsynthetic polypeptides, specifically the four naturally occurring aminoacids: L-glutamic acid, L-alanine, L-tyrosine, and L-lysine (Bornsteinet al. (1987) N Engl J Med. 317: 408-414). Copaxone® exhibits structuralsimilarity to myelin basic protein and is thought to function as animmune modulator by shifting the T helper cell type 1 response towards aT helper cell type 2 response (Duda et al. (2000) J Clin Invest 105:967-976; Nicholas et al. (2011) Drug Design, Development, and Therapy 5:255-274).

Symptom Management

Treatment of a subject with a disease modifying IFNβ agent or non-IFNβagent can be combined with one or more of the following therapies oftenused in symptom management of subjects having MS: Imuran®(azathioprine), Cytoxan® (cyclophosphamide), Neosar® (cyclophosphamide),Sandimmune® (cyclosporine), methotrexate, Leustatin® (cladribine),Tegretol® (carbamazepine), Epitol® (carbamazepine), Atretol®(carbamazepine), Carbatrol® (carbamazepine), Neurontin® (gabapentin),Topamax® (topiramate), Zonegran® (zonisamide), Dilantin® (phenytoin),Norpramin® (desipramine), Elavil® (amitriptyline), Tofranil®(imipramine), Imavate® (imipramine), Janimine® (imipramine), Sinequan®(doxepine), Adapin® (doxepine), Triadapin® (doxepine), Zonalon®(doxepine), Vivactil® (protriptyline), Marinol® (syntheticcannabinoids), Trental® (pentoxifylline), Neurofen® (ibuprofen),aspirin, acetaminophen, Atarax® (hydroxyzine), Prozac® (fluoxetine),Zoloft® (sertraline), Lustral® (sertraline), Effexor XR® (venlafaxine),Celexa® (citalopram), Paxil®, Seroxat®, Desyrel® (trazodone),Trialodine® (trazodone), Pamelor® (nortriptyline), Aventyl®(imipramine), Prothiaden® (dothiepin), Gamanil® (lofepramine), Parnate®(tranylcypromine), Manerix® (moclobemide), Aurorix® (moclobemide),Wellbutrin SR® (bupropion), Amfebutamone® (bupropion), Serzone®(nefazodone), Remeron® (mirtazapine), Ambien® (zolpidem), Xanax®(alprazolam), Restoril® (temazepam), Valium® (diazepam), BuSpar®(buspirone), Symmetrel® (amantadine), Cylert® (pemoline), Provigil®(modafinil), Ditropan XL® (oxybutynin), DDAVP® (desmopressin,vasopressin), Detrol® (tolterodine), Urecholine® (bethane), Dibenzyline®(phenoxybenzamine), Hytrin® (terazosin), Pro-Banthine® (propantheline),Urispas® (hyoscyamine), Cystopas® (hyoscyamine), Lioresal® (baclofen),Hiprex® (methenamine), Mandelamine® (metheneamine), Macrodantin®(nitrofurantoin), Pyridium® (phenazopyridine), Cipro® (ciprofloxacin),Dulcolax® (bisacodyl), Bisacolax® (bisacodyl), Sani-Supp® (glycerin),Metamucil® (psyllium hydrophilic mucilloid), Fleet Enema® (sodiumphosphate), Colace® (docusate), Therevac Plus®, Klonopin® (clonazepam),Rivotril® (clonazepam), Dantrium® (dantrolen sodium), Catapres®(clonidine), Botox® (botulinum toxin), Neurobloc® (botulinum toxin),Zanaflex® (tizanidine), Sirdalud® (tizanidine), Mysoline® (primidone),Diamox® (acetozolamide), Sinemet® (levodopa, carbidopa), Laniazid®(isoniazid), Nydrazid® (isoniazid), Antivert® (meclizine), Bonamine®(meclizine), Dramamine® (dimenhydrinate), Compazine® (prochlorperazine),Transderm® (scopolamine), Benadryl® (diphenhydramine), Antegren®(natalizumab), Campath-1H® (alemtuzumab), Fampridine® (4-aminopyridine),Gammagard® (IV immunoglobulin), Gammar-IV® (IV immunoglobulin), GamimuneN® (IV immunoglobulin), Iveegam® (IV immunoglobulin), Panglobulin® (IVimmunoglobulin), Sandoglobulin® (IV immunoglobulin), Venoblogulin® (IVimmunoglobulin), pregabalin, ziconotide, and AnergiX-MS®.

In other embodiments, the method further includes the use of one or moretherapies for management of cognitive and/or memory impairment. Examplesof such therapies include, but are not limited to, agents that increasethe level of neurotransmitters in the brain, NMDA receptor agents, andCNS stimulants (e.g., dextro or levo amphetamines).

A subject identified as a non-responder can be treated with one or moreagents described herein to manage symptoms.

Therapeutic Methods

“Treat,” “treatment,” and other forms of this word refer to theadministration of a therapy (e.g., an MS therapy), alone or incombination with one or more symptom management agents, to a subject,e.g., an MS patient, to impede progression of multiple sclerosis, toinduce remission, to extend the expected survival time of the subjectand or reduce the need for medical interventions (e.g.,hospitalizations). In those subjects, treatment can include, but is notlimited to, inhibiting or reducing one or more symptoms such asnumbness, tingling, muscle weakness; reducing relapse rate, reducingsize or number of sclerotic lesions; inhibiting or retarding thedevelopment of new lesions; prolonging survival, or prolongingprogression-free survival, and/or enhanced quality of life.

As used herein, unless otherwise specified, the terms “prevent,”“preventing” and “prevention” contemplate an action that occurs before asubject begins to suffer from the a multiple sclerosis relapse and/orwhich inhibits or reduces the severity of the disease.

As used herein, and unless otherwise specified, the terms “manage,”“managing” and “management” encompass preventing the progression ofdisease (e.g., MS) symptoms in a patient who has already suffered fromthe disease, and/or lengthening the time that a patient who has sufferedfrom the disease remains in remission. The terms encompass modulatingthe threshold, development and/or duration of MS, or changing the waythat a patient responds to the disease.

As used herein, and unless otherwise specified, a “therapeuticallyeffective amount” of a compound is an amount sufficient to provide atherapeutic benefit in the treatment or management of multiplesclerosis, or to delay or minimize one or more symptoms associated withthe disease (e.g., MS). A therapeutically effective amount of a compoundmeans an amount of therapeutic agent, alone or in combination with othertherapeutic agents, which provides a therapeutic benefit in thetreatment or management of MS. The term “therapeutically effectiveamount” can encompass an amount that improves overall therapy, reducesor avoids symptoms or causes of the disease, or enhances the therapeuticefficacy of another therapeutic agent.

As used herein, and unless otherwise specified, a “prophylacticallyeffective amount” of a compound is an amount sufficient to preventrelapse of MS, or one or more symptoms associated with the disease, orprevent its recurrence. A prophylactically effective amount of acompound means an amount of the compound, alone or in combination withother therapeutic agents, which provides a prophylactic benefit in theprevention of MS relapse. The term “prophylactically effective amount”can encompass an amount that improves overall prophylaxis or enhancesthe prophylactic efficacy of another prophylactic agent.

As used herein, the term “patient” or “subject” refers to an animal,typically a human (i.e., a male or female of any age group, e.g., apediatric patient (e.g., infant, child, adolescent) or adult patient(e.g., young adult, middle-aged adult or senior adult) or other mammal,such as a primate (e.g., cynomolgus monkey, rhesus monkey); commerciallyrelevant mammals such as cattle, pigs, horses, sheep, goats, cats,and/or dogs; and/or birds, including commercially relevant birds such aschickens, ducks, geese, and/or turkeys, that will be or has been theobject of treatment, observation, and/or experiment. When the term isused in conjunction with administration of a compound or drug, then thepatient has been the object of treatment, observation, and/oradministration of the compound or drug.

The methods described herein permit one of skill in the art to identifya monotherapy that an MS patient is most likely to respond to, thuseliminating the need for administration of multiple therapies to thepatient to ensure that a therapeutic effect is observed. However, in oneembodiment, combination treatment of an individual with MS iscontemplated.

It will be appreciated that the MS therapies, as described above andherein, can be administered in combination with one or more additionaltherapies to treat and/or reduce the symptoms of MS described herein,particularly to treat patients with moderate to severe disability (e.g.,EDSS score of 5.5 or higher). The pharmaceutical compositions can beadministered concurrently with, prior to, or subsequent to, one or moreother additional therapies or therapeutic agents. In general, each agentwill be administered at a dose and/or on a time schedule determined forthat agent. In will further be appreciated that the additionaltherapeutic agent utilized in this combination can be administeredtogether in a single composition or administered separately in differentcompositions. The particular combination to employ in a regimen willtake into account compatibility of the pharmaceutical composition withthe additional therapeutically active agent and/or the desiredtherapeutic effect to be achieved. In general, it is expected thatadditional therapeutic agents utilized in combination be utilized atlevels that do not exceed the levels at which they are utilizedindividually. In some embodiments, the levels utilized in combinationwill be lower than those utilized individually.

Systems and Computer Environment

In another aspect, the invention features a system for evaluating asubject (e.g., a patient, a patient group or a patient population). Thesystem includes at least one processor operatively connected to amemory, the at least one processor when executing is configured todetermine or calculate a value of a composite parameter associated withthe subject, wherein the processor is further configured to calculatethe value of the composite parameter responsive to establishing anattention factor for the subject and a memory factor for the subject;and evaluate the subject, based on at least one value of the compositeparameter established, e.g., prior to, during, or after the conclusionof, an MS therapy, or established responsive to administration of an MStherapy.

According to some embodiments, users (e.g., physicians, researchers,clinicians, patients, and other medical personnel) can interact withcomputer systems especially configured to monitor, manage, diagnose,prognose, and/or facilitate treatment of subjects having MS or subjectsat risk for developing MS. FIG. 3 illustrates an example process 200 fordetermining a composite parameter value for a subject, which can beexecuted on a computer system according to some embodiments. Process 200begins at 202 by establishing an attention factor for the subject beingevaluated. In some examples, the attention factor or a value for anattention factor can be input by a user based on results returned fromexternal testing or captured from information on a subject's medicalhistory. In some further examples, a computer system on which process200 is executed can be configured to execute attention testing for asubject. In some embodiments, attention testing can be delivered througha user interface of a computer system. The computer system can include aplurality of sensors configured to determine and evaluate responsivenessof a subject to test stimuli. The results of the testing can be used togenerate one or more values for an attention factor. The attentionfactor can be established at 202 by accessing and/or receiving anygenerated value for any attention factor.

In some embodiments, one or more values for the attention factor can bedetermined from the results of testing performed on a subject or by thesubject. For example, one or more values for one or more attentionfactors can be computed as the result of an assessment of complexscanning and/or visual tracking (e.g., Symbol Digit Modalities Test(SDMT)) which in some embodiments can be configured to return as aportion of its results a test score, or as a result of an assessment ofone or more of auditory information processing speed, flexibility orcalculation ability (e.g., Paced Auditory Serial Addition Test (PASAT))which in some embodiments can be configured to return as a portion ofits results a test score. A value for an attention factor can begenerated as the result of testing at 202 from any returned test score.One should appreciate that other processes for testing and scoringattention of a subject can be employed according to other embodiments.Further, other processes for testing and scoring can be used to generateone or more values for one or more attention factors.

Process 200 continues at 204 with establishing a value for a memoryfactor for the subject being evaluated. In some examples, the memoryfactor can be input by a user based on external testing. In some furtherexamples, a computer system on which process 200 is executed can beconfigured to execute a plurality of memory based tests for a subject.In some embodiments, memory testing can be delivered through a userinterface of a computer system. The results of the memory testing can beused to generate a value for a memory factor at 204. The value for thememory factor can also be established at 204 by accessing and/orreceiving the determined value for the memory factor.

In some embodiments, one or more values for a memory factor can bedetermined from the results of testing performed on a subject or by thesubject. For example, a value for a memory factor can be computed at 204as the result of an assessment of processes involved in learning and/orremembering visual information (e.g., Selective Reminding Test (SRT))which in some embodiments can be configured to return as a portion ofits results a test score, or from an assessment of visuospatial memory(e.g., Brief Visuospatial Memory Test (BVMT)) which in some embodimentscan be configured to return as a portion of its results a test score.One should appreciate that other processes for testing and scoringmemory of a subject can be employed according to other embodiments togenerate one or more values for one or more memory factors.

Process 200 continues at 206 where a composite parameter is generatedfrom the one or more values for the one or more attention factors andthe one or more values for the one or more memory factors. According toone embodiment, process 200 can be executed to calculate the compositeparameter based on a calculation of the equation: (((SDMT+(PASAT 2 andPASAT 3)/2)/2+((SRT Total Learning value+SRT Delayed Recallvalue)/2+(BVMT Total Recall value+BVMT Delayed Recall value)/2)/2)/2.The value of the composite parameter reflects improvements in theaccuracy of an assessment of a subject's mental acuity that can be usedin conjunction with detailed analysis of physical health to define anyone of progression of MS in the subject, likelihood of developing MS bythe subject, treatment options, treatment efficacy, indications forchanging treatment, among other options.

For example, FIG. 4, illustrates an example process 300 that can beexecuted on a computer system for defining correlations between acomposite parameter value and progression of MS or MS symptoms in asubject. Process 300 begins at 302 with storing a value of a compositeparameter. Step 302 can be executed repeatedly over time to establish ahistory for one or more subjects. The one or more subjects can includehealthy patients (e.g., patients showing no MS symptoms or patients notexpected to develop MS) as well as patients who may develop MS, andpatients diagnosed with MS. At 304, additional information associatedwith MS progression for a respective subject, including, for example, ahealth condition of the respective subject, can also be stored at 304for any execution of 302.

In some embodiments, the values obtained in 302 can be used to define areference value 308 YES. The reference value can be used to define abaseline level for mental acuity. At 310, a reference value can bedetermined and optionally stored for later use. In some embodiments,comparisons can be made between the reference value and compositeparameter values to determine a progression of MS, a likelihood ofdeveloping MS, efficacy of treatment for MS, to identify a need tochange MS treatment, among other options. If a reference value is notpresently being generated 308 NO or a reference value has beendetermined 310, process 300 continues at 306, where any correlationbetween the stored composite parameter values and MS progression can bedetermined. For example, composite parameter values for a first subjectcan be evaluated against subjects having a same or similar MS diagnosis.The progression of the first subject's MS can be used to predict theprogression of MS in other subjects. The evaluation can also be used toidentify a need for different or more aggressive treatment, for example,based on a prediction of worsening symptoms or outcome. In someembodiments, stored values for a plurality of subjects can be storedover time. The stored values can be used by the system to generateprobabilistic models associated with the progression of MS and effect oncognition measured by the stored composite parameters. Additionalsubjects can be evaluated by the system against the models (e.g., at310) to identify deviations from expected composite parameters definedby the models and/or the expected progression of MS for an evaluatedsubject.

Further, in some embodiments reference values determined at 310 can beincluded in the evaluation, and deviations from the reference values canbe used to evaluate progression of a subject's MS. For example,reference values can be taken and/or determined over time, e.g., at afirst and subsequent time point. Reference values determined over timecan reflect an expected change in mental acuity based, for example, onprogression of MS in a reference patient or an average progressiondetermined from a group of patients. In one embodiments, deviations fromthe expected change (e.g., a higher composite parameter value than areference score indicates improvement in the progression of thesubject's MS even, for example, where the subject's mental acuitydecreases over time (which can be reflected in analysis of the compositeparameter values alone), and a composite parameter score lower than thetime based reference indicates a worsening in the progression of thesubject's MS) can be used to confirm an treatment in progress, identifyneed for a change in treatment, identify a need for a change in a timeschedule of a treatment, etc. For example, the reference valuesdetermined over time can be used to evaluate subject over the course ofa treatment, over the progression of MS for the subject, etc.

Various embodiments according to the present invention may beimplemented on one or more specially programmed computer systems. Thesecomputer systems may be, for example, general-purpose computers such asthose based on Intel PENTIUM-type processor, Motorola PowerPC, AMDAthlon or Turion, Sun UltraSPARC, Hewlett-Packard PA-RISC processors, orany other type of processor, including multi-core processors. It shouldbe appreciated that one or more of any type computer system may be usedto perform a method of evaluating a subject having multiple sclerosis(MS), or at risk of developing MS according to various embodiments ofthe invention. Further, the system may be located on a single computeror may be distributed among a plurality of computers attached by acommunications network.

A general-purpose computer system according to one embodiment of theinvention is specially configured to perform any of the describedfunctions, including but not limited to, acquiring a value of acomposite parameter from a subject, said composite parameter comprisingan attention factor and a memory factor, identifying a subject as beingin need of an MS therapy, administering a MS therapy, monitoringadministration of an MS therapy, altering a dosing of the MS therapy,altering a schedule or a time course of a MS therapy, administering analternative MS therapy, etc. Additional functions include, for example,comparing a value of the composite parameter from the subject to areference value, performing one or more of: identifying the subject asbeing in need of an MS therapy, administering an MS therapy, altering adosing of an MS therapy, altering a schedule or a time course of an MStherapy, or selecting an alternative MS therapy responsive to adetermination of the value of the composite parameter.

It should be appreciated that the system may perform other functions,including identifying an increase in the value of the compositeparameter relative to the reference value as indicative of improvedcognitive function in the subject in response to MS therapy, determininga value of the composite parameter that differs according to theseverity of MS, wherein an increase in the value of the compositeparameter relative to the reference value, is indicative of improvedcognitive function in the subject, identifying trends in the value ofthe composite parameter based at least in part on the type of MS, forexample, in a patient having relapse remitting multiple sclerosis (RRMS)identifying patients having a lower composite parameter value comparedto a patient with secondary progressive multiple sclerosis (SPMS),wherein a decrease in the value of the composite parameter, relative toa reference value, is indicative of decreased cognitive function in asubject, evaluating one, two, three, four or more attention and memoryfactors to determine a composite parameter, wherein, for example, thememory factor is chosen from one or more verbal or visual memoryfactors.

The functions, operations, and/or algorithms described herein can alsobe encoded as software executing on hardware that together define aprocessing component, that can further define one or more portions of aspecially configured general purpose computer, that reside on anindividual specially configured general purpose computer, and/or resideon multiple specially configured general purpose computers.

FIG. 5 shows an example block diagram of a general-purpose computersystem 400 which can be especially configured to practice variousaspects of the invention discussed herein. For example, various aspectsof the invention can be implemented as specialized software executing inone or more computer systems including general-purpose computer systems604, 606, and 608 communicating over network 602 shown in FIG. 7.Computer system 400 may include a processor 406 connected to one or morememory devices 410, such as a disk drive, memory, or other device forstoring data. Memory 410 is typically used for storing programs and dataduring operation of the computer system 400. Components of computersystem 400 can be coupled by an interconnection mechanism 408, which mayinclude one or more busses (e.g., between components that are integratedwithin a same machine) and/or a network (e.g., between components thatreside on separate discrete machines). The interconnection mechanism 408enables communications (e.g., data, instructions) to be exchangedbetween system components of system 400.

Computer system 400 may also include one or more input/output (I/O)devices 402-204, for example, a keyboard, mouse, trackball, microphone,touch screen, a printing device, display screen, speaker, etc. Storage412, typically includes a computer readable and writeable nonvolatilerecording medium in which instructions are stored that define a programto be executed by the processor or information stored on or in themedium to be processed by the program.

The medium may, for example, be a disk 502 or flash memory as shown inFIG. 6. Typically, in operation, the processor causes data to be readfrom the nonvolatile recording medium into another memory 504 thatallows for faster access to the information by the processor than doesthe medium. This memory is typically a volatile, random access memorysuch as a dynamic random access memory (DRAM) or static memory (SRAM).In one example, the computer-readable medium is a non-transient storagemedium.

Referring again to FIG. 5, the memory can be located in storage 412 asshown, or in memory system 410. The processor 406 generally manipulatesthe data within the memory 410, and then copies the data to the mediumassociated with storage 412 after processing is completed. A variety ofmechanisms are known for managing data movement between the medium andintegrated circuit memory element and the invention is not limitedthereto. The invention is not limited to a particular memory system orstorage system.

The computer system may include specially-programmed, special-purposehardware, for example, an application-specific integrated circuit(ASIC). Aspects of the invention can be implemented in software executedon hardware, hardware or firmware, or any combination thereof. Althoughcomputer system 400 is shown by way of example as one type of computersystem upon which various aspects of the invention can be practiced, itshould be appreciated that aspects of the invention are not limited tobeing implemented on the computer system as shown in FIG. 5. Variousaspects of the invention can be practiced on one or more computershaving a different architectures or components than that shown in FIG.5.

It should also be appreciated that the invention is not limited toexecuting on any particular system or group of systems. Also, it shouldbe appreciated that the invention is not limited to any particulardistributed architecture, network, or communication protocol.

Various embodiments of the invention can be programmed using anobject-oriented programming language, such as Java, C++, Ada, or C#(C-Sharp). Other object-oriented programming languages may also be used.Alternatively, functional, scripting, and/or logical programminglanguages can be used. Various aspects of the invention can beimplemented in a non-programmed environment (e.g., documents created inHTML, XML or other format that, when viewed in a window of a browserprogram, render aspects of a graphical-user interface (GUI) or performother functions). The system libraries of the programming languages areincorporated herein by reference. Various aspects of the invention canbe implemented as programmed or non-programmed elements, or anycombination thereof.

Various aspects of this invention can be implemented by one or moresystems similar to system 400. For instance, the system can be adistributed system (e.g., client server, multi-tier system) comprisingmultiple general-purpose computer systems. In one example, the systemincludes software processes executing on a system associated withevaluating a subject having multiple sclerosis (MS), or at risk ofdeveloping MS according to various embodiments of the invention. Varioussystem embodiments can execute operations such as administering anassessment of processes involved in learning and/or remembering visualinformation (e.g., Selective Reminding Test (SRT)), administering anassessment of visuospatial memory (e.g., Brief Visuospatial Memory Test(BVMT)), administering an assessment of complex scanning and/or visualtracking (e.g., Symbol Digit Modalities Test (SDMT), administering anassessment of one or more of auditory information processing speed,flexibility or calculation ability (e.g., Paced Auditory Serial AdditionTest (PASAT)), or any combination of one, two, three, four, or more ofthe tests, as examples. The systems may permit physicians to access andmanage such testing, specific patient information, patient responses,patient profiles, patient analysis, etc.

There can be other computer systems that perform functions such asevaluating additional parameters chosen from one or more of quality oflife, neuropsychological evaluation, or memory function, where thesystem can administer and/or facilitate administration of testing toestablish one or more of quality of life, neuropsychological evaluation,or memory function parameters, evaluate submitted additional parameters,establish reference values from a healthy subject or an average ofhealthy subjects, a subject at different time interval, e.g., prior to,during, or after the MS therapy, a group of MS patients having the sameor different disease progressions, calculate a value of a compositeparameter for a subject from an average value of one or more memoryfactors and one or more attention factors, calculating a value of theattention factor from a score of an average of the sum of an assessmentof complex scanning and/or visual tracking and the average of at leasttwo assessments of auditory information processing speed, flexibility orcalculation ability, calculating a value of an attention factor based ondetermining {SMDT+[PASAT 3+PASAT 2]/2)}/2, wherein PASAT 3 represents adistinct execution of the PASAT test from PASAT 2, calculating a valuefor a verbal memory factor from the average of the sum of at least twoassessments of processes involved in learning and/or remembering visualinformation, averaging SRT Total Learning and SET Delayed Recall values,calculating a value for a verbal memory factor based on determining (SRTTotal Learning+SRT Delayed Recall)/2, calculating a value for a visualmemory factor from an average of at least two assessments ofvisuospatial memory, calculating a value for a visual memory factorbased on determining (BVMT Total Recall+BVMT Delayed Recall)/2,calculating a value for a memory factor from an average of a value ofthe verbal memory factor and a value of a visual memory factor,determining a reliability of a composite parameter, determining thereliability of the composite parameter to be at least one of 0.65, 0.69,0.70, 0.75, 0.80, 0.85, and higher.

These systems can also be configured to manage administration oftesting, accept as input results from testing, determine trends inevaluations, establish a statistical confidence measure based on inputresults, among other options. These systems can be distributed among acommunication system such as the Internet. One such distributed network,as discussed below with respect to FIG. 7, can be used to implementvarious aspects of the invention.

FIG. 7 shows an architecture diagram of an example distributed system600 suitable for implementing various aspects of the invention. Itshould be appreciated that FIG. 7 is used for illustration purposesonly, and that other architectures can be used to facilitate one or moreaspects of the invention. System 600 may include one or moregeneral-purpose computer systems distributed among a network 602 suchas, for example, the Internet. Such systems may cooperate to performfunctions related to evaluating a subject having multiple sclerosis(MS), or at risk of developing MS, treating a subject a subject havingmultiple sclerosis (MS), or a risk of developing MS, monitoring asubject having multiple sclerosis (MS), or at risk of developing MS,diagnosing or prognosing a subject having multiple sclerosis (MS), or atrisk of developing MS, preventing MS in a subject having multiplesclerosis (MS), or at risk of developing MS,

In an example of one such system, one or more users operate one or moreclient computer systems 604, 606, and 608 through which, for example,subjects can be administered a visual, audio, or other type of test tofacilitate scoring of various factors, or users can enter testingresults for subject, view reports on diagnosis and/or evaluation oftreatment, view suggestions on alternative therapies, etc. It should beunderstood that the one or more client computer systems 604, 606, and608 can also be used to access and/or update, for example, subjectinformation, test results, potential therapies, etc. In one example,users interface with the system via an Internet-based user interface.

In another example, a system 604 includes a browser program such as theMicrosoft Internet Explorer application program, Mozilla's FireFox, orGoogle's Chrome browser through which one or more websites can beaccessed. Further, there can be one or more application programs thatare executed on system 604 that perform functions associated withevaluating a subject having multiple sclerosis (MS), or at risk ofdeveloping MS according to various embodiments of the invention,treating, diagnosis, and/or monitoring the subject. For example, system604 may include one or more local databases for storing, caching and/orretrieving subject information associated with testing, treating,monitoring, diagnosing MS, etc.

Network 602 may also include, one or more server systems, which can beimplemented on general-purpose computers that cooperate to performvarious functions including evaluating testing results, inputtingtesting results, determining composite parameter values for a subject,evaluating treatment options based on composite parameter values,suggesting alternative therapies for a subject based on compositeparameter values, among other functions. System 600 may execute anynumber of software programs or processes and the invention is notlimited to any particular type or number of processes. Such processescan perform the various workflows and operations discussed, and can alsoinclude, for example, operations for generating reports regardingdeterminations of one or more values for a composite parameter,communicating analysis of established values of the composite parameter,communicating evaluation or treatment of a subject to a report-receivingparty or entity (e.g., a patient, a health care provider, a diagnosticprovider, and/or a regulatory agency, e.g., the FDA), acquiring andstoring values of a composite parameter including an attention factorand memory factor, in a subject (e.g., a patient, a patient group or apatient population), having multiple sclerosis (MS), or at risk fordeveloping MS, prior to, during, and/or after the MS therapy,establishing and storing values of a composite parameter including anattention factor and memory factor, in a subject (e.g., a patient, apatient group or a patient population), having multiple sclerosis (MS),or at risk for developing MS, prior to, during, and/or after the MStherapy from input data and/or data received from other systems, amongother examples.

Other features and embodiments of the invention include the following:

Additional Methods

In one aspect, the invention features a method of evaluating a subjecthaving multiple sclerosis (MS), or at risk of developing MS, comprising:acquiring a value of a composite parameter from the subject, saidcomposite parameter comprising an attention factor and a memory factor,thereby evaluating the subject, wherein responsive to a determination ofthe value of the composite parameter, the method further comprises oneor more of: (i) identifying the subject as being in need of a first MStherapy or a second (alternative) MS therapy; (ii) identifying thesubject as having an increased or a decreased response to a first MStherapy or a second (alternative) MS therapy; (iii) identifying thesubject as being stable, showing an improvement in cognitive abilities,or showing a decline in cognitive abilities; (iv) diagnosing, and/orprognosing the subject; (v) selecting or altering the course of, an MStherapy or treatment, a dose, a treatment schedule or time course,and/or the use of an alternative MS therapy, in the subject; (vi)determining a time course of MS disease progression in the subject;(vii) administering a first MS therapy or a second (alternative) MStherapy to the subject; or (viii) administering to the subject a therapyfor the management of cognitive and/or memory impairment.

In yet another aspect, the invention features a method of detectingand/or quantifying a cognitive impairment in a subject having a multiplesclerosis (MS), or at risk of developing the MS, comprising: acquiring avalue of a composite parameter from the subject, said compositeparameter comprising an attention factor and a memory factor, whereinresponsive to a determination of the value of the composite parameter,the method further comprises one or more of: (i) identifying the subjectas being in need of a first MS therapy or a second (alternative) MStherapy; (ii) identifying the subject as having an increased or adecreased response to a first MS therapy or a second (alternative) MStherapy; (iii) identifying the subject as being stable, showing animprovement in cognitive abilities, or showing a decline in cognitiveabilities; (iv) diagnosing, and/or prognosing the subject; (v) selectingor altering the course of, an MS therapy or treatment, a dose, atreatment schedule or time course, and/or the use of an alternative MStherapy; (vi) determining a time course of MS disease progression in thesubject; or (vii) administering a first MS therapy or a second(alternative) MS therapy to the subject; or (viii) administering to thesubject a therapy for the management of cognitive and/or memoryimpairment.

In another aspect, the invention features a method of treating orpreventing one or more symptoms associated with multiple sclerosis (MS),in a subject having MS, or at risk for developing MS, comprising:acquiring a value of a value of a composite parameter from the subject,said composite parameter comprising an attention factor and a memoryfactor; and responsive to said value, administering to the subject an MStherapy, in an amount sufficient to reduce one or more symptomsassociated with MS, wherein, in response to an increased value of saidcomposite parameter relative to a reference value, the MS therapy isinitiated or continued; and wherein, in response to a decreased value ofsaid composite parameter relative to a reference value, the MS therapyis modified or an alternative MS therapy is used.

In yet another aspect, the invention features a method of evaluating ormonitoring disease progression in a subject having MS, or at risk fordeveloping MS, comprising: acquiring a value of a composite parameterfrom the subject, said composite parameter comprising an attentionfactor and memory factor; and comparing the value of the compositeparameter from the subject to a reference value, wherein the value ofthe composite parameter differs according to the severity of MS, and anincrease in the value of the composite parameter, relative to thereference value, is indicative of improved cognitive function in thesubject.

Additional embodiments of the invention include one or more of thefollowing:

In certain embodiments, the value of the composite parameter is lower ina patient having with secondary progressive multiple sclerosis (SPMS)compared to a patient with relapse remitting multiple sclerosis (RRMS).In certain embodiments, an increase in the value of the compositeparameter, relative to the reference value, is indicative of improvedcognitive function in the subject. In certain embodiments, a decrease inthe value of the composite parameter, relative to the reference value,is indicative of decreased cognitive function in the subject. In certainembodiments, the value of the composite parameter is acquired byevaluating one, two, three, four or more attention and memory factors.

In certain embodiments, the memory factor is chosen from one or moreverbal or visual memory factors. In certain embodiments, the attentionand memory factors are obtained from administering one, two, three, fouror more of: (i) an assessment of processes involved in learning and/orremembering visual information, (ii) an assessment of visuospatialmemory, (iii) an assessment of complex scanning and/or visual tracking,or (iv) an assessment of one or more of auditory information processingspeed, flexibility or calculation ability.

In certain embodiments, the method further comprises evaluatingadditional parameters chosen from one or more of quality of life,neuropsychological evaluation, or memory function.

In certain embodiments, the reference value is acquired from: a healthysubject or an average of healthy subjects; the subject prior to, during,or after the MS therapy; or a group of MS patients having the same ordifferent disease progressions.

In certain embodiments, the value of the composite parameter is anaverage value of one or more memory factors and one or more attentionfactors.

In certain embodiments, the value of the attention factor is evaluatedby obtaining a score of: the average of the sum of an assessment ofcomplex scanning and/or visual tracking and the average of at least twoassessments of auditory information processing speed, flexibility orcalculation ability; or {SMDT+[PASAT 3+PASAT 2]/2)}/2.

In certain embodiments, the value of the verbal memory factor isevaluated by obtaining a score of: the average of the sum of at leasttwo assessments of processes involved in learning and/or rememberingvisual information; or (SRT Total Learning+SRT Delayed Recall)/2.

In certain embodiments, the value of the visual memory factor isevaluated by obtaining a score of: the average of at least twoassessments of visuospatial memory; or (BVMT Total Recall+BVMT DelayedRecall)/2. In certain embodiments, the value of the memory factor is theaverage of the value of the verbal memory factor and the visual memoryfactor.

In certain embodiments, the value of the composite parameter has areliability of at least 0.65, 0.69, 0.70, 0.75, 0.80, 0.85 or higher.

In certain embodiments, the subject is a patient having one of: benignMS, relapse/remitting MS (RRMS), primary progressive MS, secondaryprogressive MS (SPMS), clinically isolated syndrome (CIS), or clinicallydefined MS (CDMS). In certain embodiments, the subject has quiescentRRMS or active RRMS. In certain embodiments, the subject has secondaryprogressive MS (SPMS). In certain embodiments, the method furthercomprises treating, or preventing in, the subject having multiplesclerosis MS one or more symptoms associated with MS by administering toa subject an MS therapy, in an amount sufficient to reduce one or moresymptoms associated with MS. In certain embodiments, said treating orpreventing comprises reducing, retarding or preventing, a relapse, orthe worsening of a disability, in the MS subject.

In certain embodiments, the MS therapy comprises one or more of anIFN-β1 molecule; a polymer of glutamic acid, lysine, alanine andtyrosine; an antibody or fragment thereof against alpha-4 integrin; ananthracenedione molecule; a fingolimod; a dimethyl fumarate; an antibodyto the alpha subunit of the IL-2 receptor of T cells; an antibodyagainst CD52 or alemtuzumab; an inhibitor of a dihydroorotatedehydrogenase or teriflunomide; or an anti-LINGO-1 antibody. In certainembodiments, the IFN-β1 molecule comprises one or more of an IFN-β1a orIFN-β1-b polypeptide, a variant, a homologue, a fragment or a pegylatedvariant thereof. In certain embodiments, the MS therapy comprises anIFN-1b molecule; a polymer of glutamic acid, lysine, alanine andtyrosine; or the MS therapy comprises an alternative MS therapy chosenfrom an antibody or fragment thereof against alpha-4 integrin; adimethyl fumarate' anthracenedione molecule; a fingolimod; a dimethylfumarate; an antibody to the alpha subunit of the IL-2 receptor of Tcells; or an anti-LINGO-1 antibody.

In certain embodiments, the method further comprises one or more stepsof: performing a neurological examination, evaluating the subject'sstatus on the Expanded Disability Status Scale (EDSS), or detecting thesubject's lesion status as assessed using an MRI.

In certain embodiments, the subject is monitored in one or more of thefollowing periods: prior to beginning of treatment; during thetreatment; after the treatment has been administered; or at a first andsecond time points at least 1, 2, 3, 4, 5, or 6 months apart.

In certain embodiments, the method further comprises memorializing thevalue of the composite parameter, and/or providing a report comprisingthe memorialization.

Additional Systems and Computer-Implemented Methods

In another aspect, the invention features a system for evaluatingdisease progression in a subject having multiple sclerosis (MS), or atrisk for developing MS, comprising: at least one processor operativelyconnected to a memory, the at least one processor when executing isconfigured to: establish a value of a composite parameter associatedwith the subject reflective of cognitive function, wherein the at leastone processor is further configured to establish the value of thecomposite parameter responsive to establishing an attention factor valuefor the subject and a memory factor value for the subject; compare thevalue of the composite parameter from the subject to a reference value,and identify an indication of improved cognitive function in the subjectin response to MS therapy, wherein identifying the indication ofimproved cognitive function includes detecting an increase in the valueof the composite parameter, relative to the reference value; or identifyan indication of decreased cognitive function in the subject in responseto MS therapy, wherein identifying the indication of decreased cognitivefunction includes detecting a decrease in the value of the compositeparameter, relative to the reference value.

In certain embodiments, the at least one processor when executing isconfigured to: compute an average value of one or more memory factors todetermine the memory factor value and an average value of one or moreattention factors to determine the attention factor value; and computethe composite parameter from a combination of the memory factor valueand the attention factor value. In certain embodiments, the at least oneprocessor when executing is configured to compute an average value ofthe sum of an assessment of complex scanning and/or visual tracking andthe average of at least two assessments of auditory informationprocessing speed, flexibility or calculation ability to determine atleast a portion of the attention factor value for the subject. Incertain embodiments, the at least one processor when executing isconfigured to compute the attention factor value based on determining avalue for the equation ((Symbol Digit Modalities Test (SDMT)value+(Paced Auditory Serial Addition Test (“PASAT”) value (“PASAT1”))and a second PASAT value (“PASAT2”))/2)/2.

In certain embodiments, the at least one processor when executing isconfigured to compute at least a portion of the value of the one or morememory factors based on the average of a sum of values determined for atleast two assessments of processes involved in learning and/orremembering visual information. In certain embodiments, the at least oneprocessor when executing is configured to compute at least a portion ofthe memory factor value based on determining a value for the equation(Selective Reminding Test (“SRT”) Total Learning value+SRT DelayedRecall value)/2. In certain embodiments, the at least one processor whenexecuting is configured to compute at least the portion of the value ofthe one or more memory factors based on an average of at least twoassessments of visuospatial memory. In certain embodiments, the at leastone processor when executing is configured to compute at least theportion of the memory factor value based on determining a value for theequation (Brief Visuospatial Memory Test (“BVMT”) Total Recallvalue+BVMT Delayed Recall value)/2. In certain embodiments, the at leastone processor when executing is configured to compute at least theportion of the memory factor value based on determining the average ofthe value of a verbal memory factor and a visual memory factor from theequation ((SRT Total Learning value+SRT Delayed Recall value)/2+(BVMTTotal Recall value+BVMT Delayed Recall value)/2)/2.

In certain embodiments, the at least one processor when executing isconfigured to compute the composite value from the average of the valueof the verbal memory factor and the visual memory factor averaged withthe attention factor value calculated from the equation ((SDMTvalue+(PASAT1 and PASAT2)/2)/2. In certain embodiments, the at least oneprocessor when executing is further configured to: compute a reliabilityvalue for the composite parameter, and evaluate the reliability valueagainst a minimum threshold parameter including at least one of thethreshold parameter set for at least 0.65, 0.69, 0.70, 0.75, 0.80, 0.85or higher.

In certain embodiments, the at least one processor is configured toevaluate the composite parameter against a probabilistic model of a timecourse progression of disease effect on cognition for the subject,wherein the probabilistic model includes the reference value. In certainembodiments, the at least one processor is configured to generate theprobabilistic model of the time course progression of the disease effecton cognition for the subject including a time course of the referencevalue. In certain embodiments, the at least one processor is configuredto generate the probabilistic model from at least one population of:healthy subjects; a group of healthy subjects; the subject prior to,during, or after the MS therapy; a group of MS patients having the samedisease progressions; a group of MS patients having the differentdisease progressions; a group of MS patients having the same ordifferent disease progressions at different time intervals; a group ofMS patients undergoing different MS treatments than the subject; or agroup of MS patients undergoing a same MS treatment as the subject.

In certain embodiments, the at least one processor is configured toidentify patients having similar MS disease progression from a modelpopulation. In certain embodiments, the at least one processor isconfigured to: compute a SRT Total Learning value, SRT Delayed Recallvalue, BVMT Total Recall value, BVMT Delayed Recall value to establish amemory factor portion for the reference value; compute a SDMT value, afirst PASAT, a second PASAT value to establish an attention factorportion; and compute a combination of the memory factor portion and theattention factor portion to obtain the reference value.

In certain embodiments, the at least one processor when executing isfurther configured to: compute a reliability value for the referencevalue, and evaluate the reliability value against a minimum thresholdparameter including at least one of the threshold parameter set for atleast 0.65, 0.69, 0.70, 0.75, 0.80, 0.85 or higher. In certainembodiments, the at least one processor when executing is furtherconfigured to perform one or more of: comparing the value of thecomposite parameter from the subject to a reference value for a timeparameter defined for a course of MS progression; identifying thesubject as being in need of an MS therapy; recommending administrationof an MS therapy; determining or altering a dosing of the MS therapy;determining or altering a schedule or a time course of the MS therapy;and recommending an alternative MS therapy.

In certain embodiments, the at least one processor when executing isconfigured to determine the attention and memory factors, at least inpart, from administering, or on the results from administration, of one,two, three, four or more of: (i) an assessment of processes involved inlearning and/or remembering visual information, (ii) an assessment ofvisuospatial memory, (iii) an assessment of complex scanning and/orvisual tracking, or (iv) an assessment of one or more of auditoryinformation processing speed, flexibility or calculation ability. Incertain embodiments, the at least one processor when executing isfurther configured to: capture a plurality of values of the compositeparameter for the subject over time, and generate a model of the timecourse progression of the composite parameter, wherein the model isreflective of a disease state of the subject having MS.

In one aspect, the invention features a computer implemented method forevaluating disease progression in a subject having multiple sclerosis(MS), or at risk for developing MS, the method comprising: establishing,by a computer system, a value of a composite parameter associated withthe subject reflective of cognitive function, wherein establishing thevalue of the composite parameter includes establishing an attentionfactor value for the subject and a memory factor value for the subject;comparing, by the computer system, the value of the composite parameterfrom the subject to a reference value, and identifying, by the computersystem, an indication of improved cognitive function in the subject inresponse to MS therapy, wherein identifying the indication of improvedcognitive function includes detecting an increase in the value of thecomposite parameter, relative to the reference value; or identifying, bythe computer system, an indication of decreased cognitive function inthe subject in response to MS therapy, wherein identifying theindication of decreased cognitive function includes detecting a decreasein the value of the composite parameter, relative to the referencevalue.

In certain embodiments, establishing an attention factor value for thesubject and a memory factor value for the subject includes: computing anaverage value of one or more memory factors to determine the memoryfactor value; computing an average value of one or more attentionfactors to determine the attention factor value; and computing thecomposite parameter from a combination of the memory factor value andthe attention factor value. In certain embodiments, the method furthercomprises computing an average value of the sum of an assessment ofcomplex scanning and/or visual tracking and the average of at least twoassessments of auditory information processing speed, flexibility orcalculation ability to determine at least a portion of the attentionfactor value for the subject. In certain embodiments, establishing theattention factor value for the subject includes computing the attentionfactor value based on determining a value for the equation ((SymbolDigit Modalities Test (SDMT) value+(Paced Auditory Serial Addition Test(“PASAT”) value (“PASAT1”)) and a second PASAT value (“PASAT2”))/2)/2.

In certain embodiments, the method further comprises computing at leasta portion of the value of the one or more memory factors based on theaverage of a sum of values determined for at least two assessments ofprocesses involved in learning and/or remembering visual information. Incertain embodiments, the method further comprises computing at least aportion of the memory factor value based on determining a value for anequation (Selective Reminding Test (“SRT”) Total Learning value+SRTDelayed Recall value)/2. In certain embodiments, computing at least theportion of the value of the one or more memory factors based on theaverage of the sum of values determined for at least two assessments ofprocesses involved in learning and/or remembering visual informationincludes computing at least the portion of the value of the one or morememory factors based on an average of at least two assessments ofvisuospatial memory.

In certain embodiments, computing at least the portion of the memoryfactor value includes computing at least the portion of the memoryfactor value based on determining a value for the equation (BriefVisuospatial Memory Test (“BVMT”) Total Recall value+BVMT Delayed Recallvalue)/2. In certain embodiments, computing at least the portion of thememory factor value includes determining the average of the value of averbal memory factor and a visual memory factor from the equation ((SRTTotal Learning value+SRT Delayed Recall value)/2+(BVMT Total Recallvalue+BVMT Delayed Recall value)/2)/2. In certain embodiments,establishing the value of the composite value includes computing thecomposite value from the average of the value of the verbal memoryfactor and the visual memory factor averaged with the attention factorvalue calculated from the equation ((SDMT value+(PASAT1 andPASAT2)/2)/2.

In certain embodiments, the method further comprises computing areliability value for the composite parameter, and evaluating thereliability value against a minimum threshold parameter including atleast one of the threshold parameter set for at least 0.65, 0.69, 0.70,0.75, 0.80, 0.85 or higher.

This invention is further illustrated by the following examples whichshould not be construed as limiting. The contents of all references,figures, sequence listing, patents and published patent applicationscited throughout this application are hereby incorporated by reference.

EXEMPLIFICATION

Cognitive impairment is common in MS patients, with frequencies rangingfrom 40-75% reported in clinical samples (Rao et al. (1995) Curr Opin inNeurol 8: 216-220; Fischer et al. (1994) Neurorehabil Neural Repair 8:151-164; Lyon-Caen et al. (1986) Arch Neurol 43: 1138-1141; Peyser etal. (1980) Arch Neurol 37: 577-579) and meta-analyses (Wishart et al.(1997) Journal of Clinical and Experimental Neuropsychology 19: 810-824;Thornton et al. (1997) Neuropsychology 11: 357-366; Prakash et al.(2008) Multiple Sclerosis 14: 1250-1261), with estimates varyingaccording to the definition of cognitive impairment. Processing speedand learning/memory are the domains identified as most likely to beimpaired in individual MS subjects with frequency rates estimated atapproximately 52% and 54%, respectively (Rao et al. (1991) Neurology 41:685-91; Benedict et al. (1996) Psychological Assessment 8: 145-153), andmay co-occur or be observed independently. Cognitive impairments inacquired visual and verbal memory; working memory; executive functions,e.g., planning, organizing, and initiation; perceptual processing;fluency; visuospatial perception; speed; and concept formation are alsocommonly associated with MS (Chiaravalloti and DeLuca (2008) The LancetNeurology, Volume 7 (12):1139-1151).

Loss of cognitive function occurs early on in active MS (Cadavid et al.(2011) Multiple Sclerosis Journal, 17: 1113-1121), and has been shown tosignificantly impact numerous areas of daily life including, employment,social and vocational activities, household activities, sexualfunctioning, family activities, overall quality of life, and psychiatrichealth (Rao et al, ((1991) Neurology 41(5):685-691). These cognitiveimpairments are relatively independent of the MS associated motorimpairments ((Chiaravalloti and DeLuca (2008) supra). A pharmaceuticaltherapy that improved cognitive functioning in MS patients wouldtherefore be of considerable value in the overall management of MSsymptoms. However, in order to assess the effectiveness ofpharmaceutical interventions, reliable and valid indices of meaningfulcognitive change are required.

The Multiple Sclerosis Functional Composite (MSFC) has been deemed aclinically meaningful measure of disability in MS patients (Polman etal. (2010) Neurology, 74: 8-S15). However, while the measure has beenshown to be sensitive to neurologic deterioration in general, it was notdesigned to monitor cognitive improvement or deterioration out of thecontext of more general improvement or decline. Further, the MSFC islacking any measure of learning and memory, and is thus inadequate as acomposite representation of cognitive functioning in MS patients whopresent with cognitive impairment in learning and memory, but notprocessing speed. In addition, the MSFC is further disadvantageous as itconsists of a lengthy battery of tests, which must be administered by aneuropsychologist. Adequate assessment of MS cognitive impairment isconfounded by the fact that the severity of cognitive disability in MScan be subtle to moderate, and the occurrence and patent of cognitivedysfunction are variable.

A composite endpoint which summarizes multiple domains of observationsinto a single index of overall functioning offers advantages, includingincreased sensitivity, greater statistical power and smaller samplesize, greater simplicity in summarizing treatment effects, and relatingthe relevance of those effects. The current example establishes thesensitivity to impairment, reliability, validity, and psychometricproperties of a cognitive composite parameter for use in patientevaluation and research on pro-cognitive pharmaceutical interventions inthe MS population.

Example 1 Construction of MS Cognitive Composite Parameter

Cognitive Test Selection

The individual tests selected as component measures of the finalcomposite parameter included broadly the Paced Auditory Serial AdditionTest (PASAT), Selective Reminding Test (SRT), Symbol Digit ModalitiesTest (SDMT), and the Brief Visuospatial Memory Test-Revised (BVMT-R).Specifically, the six-trial format of the SRT was selected with Hannayand Levin's word lists for adults, forms 1 and 3. Two alternate versions(PASAT 2″ and PASAT 3″) were selected for the PASAT; and the oralversion of the SDMT was selected. The PASAT and SDMT are measures ofworking memory and processing speed, the SRT is a measure ofauditory/verbal learning and memory, and the BVMT-R is a measure ofvisual learning and memory. Component tests were selected based on thesensitivity of the proposed component tests to memory and processingspeed deficits in MS patients, test-retest reliability, the availabilityof multiple alternate forms for longitudinal studies, suitability foradministration by trained clinical staff, and the potential for use incross-cultural settings.

The individual component tests have been used in multiple clinicaltrials for evaluation of cognitive disabilities and the assessment oftherapeutic regimens on cognitive function. For example, the PSAT hasbeen used to evaluate the effect of Avonex® on cognitive impairment(Fischer et al, (2000) Ann Neurol, 48: 885-92) and the effect of Avonex®on cognitive impairment in SPMS subjects in the IMPACT trial (FIG. 1A;Cadavid et al, AAN 2010 Toronto); the effect of Rituxan® in PPMSsubjects in the OLYMPUS trial (FIG. 1B); and the effect of Tysabri® oncognitive impairment in the AFFIRM trial. The SDMT has been used toevaluate the effect of tysabri on cognitive impairment in the STRATAtrial (Morrow, ECTRIMS, 2009). In addition, the SDMT has been usedevaluate the effect of acute relapses on cognition in MS (Morrow et al,(2001) J Neurol, 258: 1609).

Participants

Participants were recruited from four centers in New York and NewJersey, each recruiting 15 patients with a documented history ofRelapsing-Remitting or Secondary Progressive MS. Participants wereincluded regardless of MS severity, the presence of cognitiveimpairment, or duration of illness; so as to be representative of thegeneral MS patient population. Exclusion criteria included physical orsensory impairment that might preclude completion of cognitive testprotocols, untreated major depressive disorder, untreated anxietydisorder, history of severe psychiatric illness, severe traumatic braininjury, a medical illness that would preclude successful completion ofthe assessments, history of serious infection within 2 months prior toStudy Day 1, use of marijuana within 2 months prior to Study Day 1 or atany time during the study, or relapse within two months of start date.All patients were native English speakers.

Demographic characteristics of the sample identified the group astypical of clinical MS populations. The group was comprised of 43 women(72%) and 16 men (28%) recruited from lists of patients diagnosed withMS according to McDonald criteria in 4 northeastern U.S. clinics, withan average age of 47.9 (sd=7.9; range=26-61). Except for one subject whowas excluded because of the onset of clinically significant symptoms ofdepression following Study Day 1, all patients were neurologically andpsychiatrically stable for the duration of the study. A majority (77%)were receiving disease modifying therapy. Average time since diagnosiswas 13.2 years (d.s.=8.5; range=1-33). Similar to reported studies ofother clinical MS populations, the majority (87%) were Caucasian, with5% identifying as African-American, 5% as Hispanic, and 3% as Other.Approximately 77% of participants had a diagnosis of Relapsing-RemittingMS and 23% a diagnosis of Secondary Progressive MS. The median EDSS was2.5 and the mode was 2. Only 2% were not high school graduates, with 27%having a high school degree or GED, 18% an Associates Degree, 28% aBachelors Degree, 21% a Masters Degree, and 5% an advanced degree.

Assessment Procedures

Participants were assessed at two time points, approximately 45 daysapart. Each participant completed the SDMT Oral Version, PASAT, BVMT-R,and SRT on each occasion. Order of test administration was thefollowing: SRT Learning Trials, SDMT, PASAT 3- and 2-second trials, theWechsler Adult Intelligence Scale-IV Matrix Reasoning subtest, SRTDelayed Recall, and BVMT-R Delayed Recall. The Wechsler AdultIntelligence Scale-IV Matrix Reasoning subtest was included as anestimate of premorbid intelligence, and to allow the desired intervalbetween learning and delay trials on memory measures. The testinstruments used for each component test are described above. Total timefor administration was approximately 30 minutes.

Equivalent alternate forms were used to minimize form-specific practiceeffects. Forms were administered in the same order to all subjects.Results were scored by a central rater to ensure consistency andsubsequently double entered into an electronic database. For the SDMT,the original WPS-published form was administered at Study Day 1 and theRao's Form 2 was administered at Study Day 2 (Smith et al. (1982) Symboldigit modalities test: Manual. Los Angeles: Western PsychologicalServices; Rao et al. (1991) Neurology 41: 685-691).

Test Instruments

Symbol Digit Modalities Test (SDMT)

In this measure of processing speed and working memory, the subject isgiven 90 seconds to pair specific numbers with given geometric figuresbased on a reference key using an oral response, to limit problems dueto dexterity in MS patients (Rao SM. Neuropsychological ScreeningBattery for Multiple Sclerosis: National Multiple Sclerosis Society;1991b). At Study Day 1 the original, WPS-published form was administeredand at Visit 2 Rao's Form 2 was administered ((Smith A. Symbol digitmodalities test: Manual. Los Angeles: Western Psychological Services;1982); (Rao SM. A Manual for the Brief, Repeatable Battery ofNeuropsychological Tests in Multiple Sclerosis: National MultipleSclerosis Society; 1991a)).

Paced Serial Addition Test (PASAT)

First developed by Gronwall to assess patients recovering fromconcussion, the PASAT requires patients to monitor a series of 61audiotaped digits while adding each consecutive digit to the oneimmediately preceding it (Gronwall DMA. Perceptual and Motor Skills1977; 44:367-73). The number of intervals and presentation rates weresubsequently modified by Rao and colleagues calling for two trials, withinter-stimulus intervals of 3 and 2 seconds, respectively (Rao SM. AManual for the Brief, Repeatable Battery of Neuropsychological Tests inMultiple Sclerosis: National Multiple Sclerosis Society; 1991a). Rao'sForm 1 and 2 were administered at Study Day 1 and 2, respectively.

Selective Reminding Test

The history of this test begins with the work of Buschke et al whoconducted research in the area of anterograde amnesia (Buschke F.Neurology. 1974; 24:1019-25). After the examiner reads a list of 12target words on an initial learning trial, the test-taker is asked totry to repeat the entire list. On 5 subsequent learning trials, the SRTrequires the experimenter to repeat only target words not recalled bythe subject on the previous trial, and test-taker is asked to repeat theentire list. A delayed recall trial is included. Hannay and Levin's wordlists for adults, Forms 1 and 3, were selected for this study based onavailable research (Hannay H J, Levin H S. Journal of clinical andexperimental neuropsychology. 1985; 7).

Brief Visuospatial Memory Test-Revised

The Brief Visuospatial Memory Test-Revised (BVMT-R) is based on aninitial effort to develop equivalent alternate form visual memory tests((Benedict RHB. Neuropsychological Rehabilitation. 1993; 3:37-51);Benedict RHB. The Clinical neuropsychologist. 1995; 9)). In the revisedversion, the BVMT-R includes three 10-sec exposures to the stimulus(Benedict RHB. Brief Visuospatial Memory Test-Revised: ProfessionalManual. Odessa, Fla.: Psychological Assessment Resources, Inc.; 1997);(Benedict RHB. Psychological Assessment. 1996; 8:145-53)). After eachexposure, the subject is asked to reproduce the matrix with using apencil on a blank sheet of paper. Further, there is extensive researchshowing that all 6 forms of the test are of equivalent difficulty.Variables of interest in the current study were the Total Learning andDelayed Recall scores.

Memory Functioning Questionnaire

The Memory Functioning Questionnaire was designed to examineself-reported memory complaints (Gilewski M J. Psychology and aging.1990; 5). It consists of 64 items addressing memory difficulty andfrequency of forgetting, presented in 7 sections, each rated on a7-point scale.

MS Neuropsychological Questionnaire

The MSNQ is a 15-item report schedule with versions developed both forpatient- and informant-reports of cognitive and neuropsychiatricsymptoms commonly observed in the MS population (Benedict RH. Multiplesclerosis. 2003; 9).

MS Quality of Life-54

The MSQOL-54 was developed by combining the most widely utilized genericmeasure of quality of life in the world, the SF-36, with additionalitems specific to MS.

Data Analysis

Analyses were completed using SPSS software. Two participants did notcomplete PASAT 2″ at the initial visit after becoming overly frustrated.All raw scores were converted into demographically adjusted z scoresusing a single peer-reviewed US-database of control subjects similar inage, gender and education to the study group, which (Strober et al.(2009) Mult Sclerosis, 15: 1077-1084) were used for all analyses.Reliability was investigated using Pearson r correlations. Based on apriori assumptions based on existing literature (see e.g., Lezak et al.,2006, the PASAT and SDMT were combined into a processing speed (PS)factor and the SRT and BVMT-R combined into a learning and memory (LM)factor, which were examined using loadings on factor analysis asdetailed below. The factors and composite parameter per se wereconstructed according to clinical usage as detailed below. An a prioricutoff of 0.70 was established as indicative of minimally acceptablereliability.

Component Measurements

Each component measure revealed sensitivity to cognitive impairment inthe clinical sample. Standardized summary scores for cognitive indicesidentified as clinically sensitive by Strober et al. (see Strober et al.(2009) Mult Sclerosis, 15: 1077-1084) were computed based on thatresearcher's normative control data, which included all the measures ofinterest. Average performance across subtests was well below the controlz score mean of 0 and ranged from −0.62 to −1.7 (Table 1). Prevalence ofimpairment as defined by a score of −1.5 or −1.0 standard deviationsbelow the control mean or greater, ranged from 26% to 54% for the formerand from 36% to 61% for the latter (Table 1). Each component measurealso displayed good test-retest reliability as shown in Table 2.

The standardized summary scores were entered into a factor analysis.Eigenvalues of 4.43 and 1.04 identified two factors accounting for atotal of 78% of the variance. All combinations of estimation method(principal axis factoring, maximum likelihood), rotation procedure(orthogonal vs. oblique), and extraction criteria (all factors witheigen values>1 vs. only the first two factors) were explored in order toexplore the stability of the factors analysis. Varimax rotation withKaiser normalization identified factor one as comprised of loadings ofSRT Total Learning and Delayed Recall and BVMT-R Total Learning andRecall, with loadings ranging from 0.74 to 0.85 (Table 3). Factor 2 wascomprised of SDMT, PASAT 3″ and PASAT 2″ (also referred to herein asPASAT 3 and PASAT 2, respectively) with loadings ranging from 0.57 to0.95. These factors were labeled Learning and Memory (LM) Factor andProcessing speed (PS) Factor, accordingly.

TABLE 1 Average Performances and Frequency of Cognitive Impairment onIndividual Component Measures, Relative to Normative Control. MeasureMean Z Score % < −1.5 Std Dev SDMT −1.1 36 PASAT 3 −.7 27 PASAT 2 −.6226 SRT Total −.75 29 SRT Delay −.80 34 BVMT-R Total −1.3 53 BVMT-R Delay−1.7 54

TABLE 2 Reliability for Individual Component Measures. Measure Pearson rSDMT 0.88 PASAT 3 0.85 PASAT 2 0.87 SRT Total Recall 0.70 SRT DelayedRecall 0.62 BVMT-R Total Recall 0.82 BVMT-R Delayed Recall 0.83

TABLE 3 Rotated Component Matrix - Principal Component Analysis,Rotation Method: Varimax with Kaiser Normalization. Component Factor 1 2SDMT 0.586 0.567 PASAT 3″ 0.308 0.891 PASAT 2″ 0.178 0.942 SRT Learning0.744 0.420 SRT Delayed Recall 0.831 0.099 BVMT-R Total Learning 0.8540.280 BVMT-R Delayed Recall 0.817 0.295

Factor Construction

The standardized summary scores were entered into a factor analysis.Eigen values of 4.43 and 1.04 identified two factors accounting for atotal of 78% of the variance. Varimax rotation with Kaiser normalizationidentified factor 1 as comprised of loadings of SRT Total Learning, SRTDelayed Recall, BVMT-R Total Learning, and BVMT-R Recall, with loadingsranging from 0.74 to 0.85. Factor 2 was comprised of SDMT, PASAT 3″, andPASAT 2″, with loadings ranging from 0.57 to 0.95. Factor 1 was labeledas learning and memory (LM) factor and factor 2 as the processing speed(PS) factor.

The LM factor was constructed by averaging the standard scores for the 4component indices (SRT Total Learning, SRT Delayed Recall, BVMT-R TotalLearning, and BVMT-R Recall), thus giving equal weightings both toverbal and visual memory as well as to both learning and delayed recallscores. This plan was in keeping with each indices' roughly equivalentsensitivity to cognitive impairment in MS patients as detailed byStrober et al. (see Strober et al. (2009) Mult Sclerosis, 15:1077-1084). For the PS composite, the two PASAT total scores (PASAT 3″and PASAT 2″) were averaged and then subsequently averaged with the SDMTscore, so as to give equal weightings to these different paradigms(PASAT 3″ and PASAT 2″), as well as to reflect Strober's finding thatthe SDMT has relatively greater sensitivity to cognitive impairment (seeStrober et al. (2009) Mult Sclerosis, 15: 1077-1084). A total compositewas constructed by averaging the LM and PS composites with equalweighting. FIG. 2 diagrams the methodology of the total compositeparameter construction.

Evaluation of the Factors and Composite Parameter

The sensitivity of the factors and the composite parameter to impairmentwas evident in the mean z scores ranging from z=−1 to z=−1.8 (Table 4),with the frequency of impairment being comparable to the numerouspreviously reported studies. Reliability of the factors and thecomposite parameter were considered excellent, with greater reliabilityassociated with the composite score as reported in Table 5.

TABLE 4 Severity and Frequency of Impairment by MS Subtype for FactorScores and the Composite Parameter Score. Factor Mean Z Score % < −1.5Std Dev % < −1 Std Dev Processing Speed −1.0 34 48 Memory −1.8 57 64Composite −1.7 62 77

TABLE 5 Reliability for Factor scores and the Composite Parameter Score.Index Pearson r Learning and Memory Factor 0.86 Processing Speed Factor0.89 Composite 0.91

Psychometric characteristics of the composite parameter score were alsoanalyzed, as it was anticipated that the measure will be used as anendpoint in pharmaceutical trials. As illustrated in Table 6, thecomposite parameter score showed good sensitivity to impairmentparticularly given that the sample is a clinical one, as indicated bythe mean z score of −1.1 at Visit 1 and the normal distribution. Apractice effect of 0.35 standard deviation was evident at Visit 2,although the strong reliability demonstrated by the composite scoreindicates that this is not an obstacle to detecting change in cognitivefunctioning in a pharmaceutical trial. Moreover, this retest effect isconsistent with similar effects previously reported (see summary, Spreenand Strauss).

TABLE 6 Psychometric Characteristics of the Composite Parameter at Visit1 and Visit 2. Statistic (Z scores) Composite Score: Visit 1 CompositeScore: Visit 2 Mean −1.1 −.75 St Dev 1.3 1.1 St Error of Mean .17 .14Range −4.1 to 1.3 −3.1 to 1.2 Skewness −.37 −.35 Kurtosis −.61 −.77

To examine the clinical character of the composite parameter score, theseverity and frequency of impairment were compared across theRelapsing-Remitting MS (RRMS) and Secondary Progressive MS subgroups(SPMS). As would be expected, those participants with SecondaryProgressive MS had cognitive impairment of greater severity and weremore frequently impaired on both composites and on the compositeparameter score as shown in Table 7. Reliability scores according to MSsubtype were excellent, with Secondary Progressive MS participantsgenerally demonstrating somewhat greater reliabilities as shown in Table8.

TABLE 7 Severity and Frequency of Impairment by MS Subtype for Factorscores and the Composite Parameter Score. % < −1.5 % < −1 Factor MS TypeMean Z Score Std Dev Std Dev Processing RR −1.0 34 48 Speed SP −1.8 6262 Learning and RR −.96 33 42 Memory SP −1.8 57 64 Composite RR −.96 3739 Endpoint SP −1.7 62 77

TABLE 8 Reliability coefficients for the Factor and Composite ParameterScores Reliabilities by MS Subtype group Factor MS Type Pearson rProcessing RR 0.88 Speed SP 0.90 Learning and RR 0.82 Memory SP 0.91Composite RR 0.90 Endpoint SP 0.93

The study further evaluated the relationships between the compositeendpoint parameter and the patient recorded outcomes (PROs), includingthe Mental Competent Summary (MSQOL (SF-36)), the Memory FunctioningQuestionnaire, (MFQ), and the Multiple Sclerosis NeuropsychologicalQuestionnaire (MSNQ) (Table 9), and across the Relapsing-Remitting MSand Secondary Progressive MS subgroups as shown in Tables 10-12, asMSQOL, MFQ, and MSNQ could potentially serve as co-primary endpoints tothe composite endpoint parameter in a clinical trial setting. PROs inboth RRMS and SPMS showed excellent reliability. However, the PROs onSPMS subjects were found to be reliable but not valid. Unlike subjectreports, the MSNQ informant reports alone were found to be reliablebecause they correlated with actual cognitive performance on theobjective test with the cognitive composite battery.

TABLE 9 Test-Retest Correlations for Patient (PROs) or Informant (IROs)reported outcomes. All tests were found to be reliable based on highPearson r values. Subtest Pearson r MFQ General Forgetting .89 MSQOL(Physical Health) .88 MSQOL (Mental Health) .87 MSNQ-Patient .81MSNQ-Informant .88

TABLE 10 RRMS versus SPMS Reliabilities for PROs. All tests were foundto be reliable based on high Pearson r values, both in RRMS and SPMS.Pearson r with Subtest MS TYPE Composite MFQ General Forgetting RR 0.88SP 0.87 MSQOL RR 0.94 (Physical Health) SP 0.94 MSQOL RR 0.92 (MentalHealth) SP 0.92 MSNQ-Patient RR 0.75 SP 0.92 MSNQ-Informant RR 0.86 SP0.75

TABLE 11 RRMS vs. SPMS Correlation: PROs with Cognitive CompositeParameter 1. Notice that only the MSNQ-informant showed a correlationwith the actual cognitive performance. r with Pearson r with SubtestComposite MS TYPE Composite MFQ General Forgetting 0.08 RR 0.14 SP −0.05MSQOL (Physical Health) 0.16 RR 0.36 SP −0.36 MSQOL (Mental Health) 0.17RR 0.35 SP −0.40 MSNQ-Patient −0.04 RR −0.19 SP 0.35 MSNQ-Informant−0.33 RR −0.37 SP −0.21

TABLE 12 RRMS vs. SPMS Correlation: PROs with Cognitive CompositeParameter 2. Notice that the patient reported outcomes did correlatewith actual performance in RRMS but not in SPMS. Only the informantreports did correlate with actual performance in SPMS. r with Pearson rwith Subtest Composite MS TYPE Composite MFQ General Forgetting 0.20 RR0.39 SP −0.11 MSQOL (Physical Health) 0.27 RR 0.44 SP −0.16 MSQOL(Mental Health) 0.22 RR 0.35 SP −0.15 MSNQ-Patient −0.20 RR −0.38 SP0.13 MSNQ-Informant −0.39 RR −0.40 SP −0.37

Evaluation of Composite Parameter Endpoint

This study established the reliability of the proposed compositeparameter for MS generally and for SPMS patients specifically. Thecomposite parameter endpoint identified 62% to 77% of patients as havingclinically significant cognitive impairment, which is similar toestimated rate of 55 to 75% prevalence reported in clinical samplesusing more comprehensive test batteries (see, Rao et al. (1995) CurrOpin in Neurol, 8: 216-20; Fischer et al. (1994) Neurorehabil NeuralRepair, 8: 151-164; Lyon-Caen et al. (1986) Arch Neurol,43(11):1138-1141; Edwards et al. (1980) Arch Neurol, 37: 577-579).Further, the PS and LM composites revealed sensitivities of 48% and 68%,respectively, which are similar to previously reported clinical sampleestimates of 52% and 54% (see, Rao et al. (1991) Neurology, 41: 685-91;Benedict et al. (1996) Psychological Assessment 8: 145-153). Moreover,the frequency of impairment in the borderline or lower ranges identifiedby the Composite endpoint was maintained or increased modestly relativeto the LM and PS composites, indicating that in this batterymultidimensional assessment is likely preferable to individual domainsfor a pharmaceutical trial in which change in generalized cognitiveability is of interest. In this light, it is noted that findings ofimpairment in multiple domains if preferable to single domains indiagnosis of a cognitive impairment syndrome. Further, the Compositeendpoint revealed greater frequency of impairment in patients with SPMSvs. RRMS, in keeping with the greater disease severity associated withthe former population as documented in numerous research studies((Benedict RHB. Journal of the International Neuropsychological Society.2006; 12:549-58); Strober L. Multiple sclerosis. 2009; 15(9):1077-8);DeLuca J. Journal of clinical and experimental neuropsychology. 2004;26(4):550-62)). This observation further supports the compositeparameter endpoint as a reasonable surrogate in regard to sensitivity tocognitive impairment in MS compared to larger, broader test batteries.Study completion was excellent and supporting its use in multicentertrials.

In addition, the composite parameter demonstrated excellent test-retestreliability with a Pearson r value of 0.91, which was better than orsimilar to reports for the component subtests; although this was notunexpected given that an increased number of observations can provide amore stable basis for improved reliability. The composite parameter alsodemonstrated a normal distribution with no evidence of significant skewor kurtosis and a standard deviation close to that of a non-impairedpopulation (z=1.3 for Visit 1; z=1.1 for Visit 2), an important featurefor estimating sample sizes for large pharmaceutical trials. Similarly,the standard error of the mean of the composite parameter score wassmall compared to the standard deviation, indicating excellent potentialfor accuracy in assessment of each patient. Patient reported outcomeswere not accurate predictors of objective measures of cognitivefunction.

Importantly, the psychometric methodology for establishing the PS and LMcomposites was strongly supported. Even in this relatively small samplesize, factor analysis identified two and only two factors which, uponinspection, were comprised of the proposed component subtests in therespective cognitive domains. Within each cognitive domain, the SDMTshowed somewhat greater sensitivity than the PASAT, and the BVMT-Rshowed somewhat greater sensitivity than the SRT. These observationshave been reported in previous studies, suggesting the data collected inthis study was representative of a typical MS clinical sample.

Use of the Composite endpoint in a drug development clinical trial ispreferable to methodologies used in past drug studies and currentclinical practice. The Composite endpoint also is preferable to thelarge battery of tests administered by Fischer et al in English speakingsubjects from the Avonex® phase 3 trial in regard to practicality, andalso to the subset of tests identified in that research as sensitive tochange in MS in regard to availability of alternate forms and validationof component subtests (Fischer. Annals of neurology. 2000;48(6):885-92). Further, the Composite has psychometric support forcombination of component subtests which was not the case in the Fischeret al., research which was guided by clinical judgment. Given furtherresearch support and the specific nature of the research question beinginvestigated, use of the Composite might be preferred to the use ofcurrent clinical batteries such the MACFIMS and BRB ((Benedict RH. TheClinical neuropsychologist. 2002; 16(3):381-97); Rao SM. Neurology.1991; 41:695-1)). That is, while the MACFIMS might serve well as acomprehensive assessment in clinical settings, it is far lengthier andhas only one alternate form. It is noted that 3 of the 4 tests includedin the current Composite endpoint are included in the MACFIMS,identifying the Composite endpoint as an alternative potentially moresuitable for international multi-center pharmaceutical trials in MS dueto its relative brevity, repeatability, and its status as a singleoutcome. In further support of the acceptability of the subtestscomprising the Composite is the selection of some of its components byboth BICAMS and the NINDS CDE Task Force (Langdon D W. Multiplesclerosis. 2012; 18(6):891-8). Finally, the subtest components of theproposed Composite are easily administered by trained study personneland not just by neuropsychologists, facilitating feasibility in largeinternational clinical trials. For example, in the current study, testadministrators included trained and supervised psychology graduatestudents and nurses as well as neuropsychologists.

The poor correlations between patient- and informant-reportedneuropsychological symptoms and objective performance on the Compositeendpoint was not unexpected as previous researchers have made similarobservations (Benedict RH. Multiple sclerosis. 2003; 9(1):95-101). Thisstudy showed, inter alia, first, RRMS subjects were clearly better ableto perceive their neuropsychological symptoms, as their self-appraisalswere moderately correlated with their overall performance, whereasself-appraisals of SPMS subjects consistently lacked meaningfulassociation with their test performances. This is consistent with theobservation that self-assessment and insight into symptoms worsens withthe severity of cognitive impairment. Second, as has been notedpreviously, informants are reasonably accurate reporters of MS cognitiveproblems (Benedict RH. Multiple sclerosis. 2003; 9(1):95-101). Based onthe present results, the proposed Composite Cognitive endpoint has apsychometric basis, sensitivity similar to a larger and broader batteryof tests, a normal distribution of scores, and excellent test-retestreliability.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned herein arehereby incorporated by reference in their entirety as if each individualpublication, patent or patent application was specifically andindividually indicated to be incorporated by reference. In case ofconflict, the present application, including any definitions herein,will control.

Also incorporated by reference in their entirety are any polynucleotideand polypeptide sequences which reference an accession numbercorrelating to an entry in a public database, such as those maintainedby The Institute for Genomic Research (TIGR) on the worldwide web attigr.org and/or the National Center for Biotechnology Information (NCBI)on the worldwide web at ncbi.nlm.nih.gov.

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed.

What is claimed is:
 1. A method of treating or preventing multiple sclerosis (MS), in a subject having MS, or at risk of developing MS, comprising: acquiring a value of a composite parameter from the subject, said composite parameter comprising a first value for an attention and/or processing speed (PS) factor and a second value for a memory factor, wherein: (i) the first value is acquired by obtaining a score from at least two assessments indicative of attention and/or processing speed, and (ii) the second value is acquired by obtaining a score from at least one assessment of auditory/verbal learning and memory, and at least one assessment of visual learning and memory; and responsive to said value, administering to the subject an MS therapy in an amount sufficient to reduce one or more symptoms associated with MS, wherein, in response to an increased value of said composite parameter relative to a reference value, the MS therapy is initiated or continued; and wherein, in response to a decreased value of said composite parameter relative to a reference value, the MS therapy is modified or an alternative MS therapy is used.
 2. A method of evaluating and/or quantifying cognitive function in a subject having multiple sclerosis (MS), or at risk of developing MS, comprising: acquiring a value of a composite parameter from the subject, said composite parameter comprising a first value for an attention and/or processing speed (PS) factor and a second value for a memory factor, wherein: (i) the first value is acquired by obtaining scores from at least two assessments indicative of attention and/or processing speed, and (ii) the second value is acquired by obtaining a score from at least one assessment of auditory/verbal learning and memory, and at least one assessment of visual learning and memory; and (optionally) comparing the value of the composite parameter from the subject to a reference value, wherein an increase in the value of the composite parameter, relative to a reference value, is indicative of improved cognitive function in the subject, and wherein a decrease in the value of the composite parameter, relative to a reference value, is indicative of decreased cognitive function in the subject.
 3. The method of claim 1 or 2, wherein the first value is obtained by one or more of: (i) averaging the scores from at least one assessment of complex scanning and/or visual tracking, and at least one or two assessment(s) of processing speed, flexibility and/or calculation ability; (ii) as a function of a score based on a Symbol Digit Modalities Test (SMDT)) and a score based on at least one or two Paced Auditory Serial Addition Test (PASAT); or (ii) calculating the first value using the following equation: {SMDT score+[PASAT 3 score+PASAT 2 score]/2)}/2.
 4. The method of any of claims 1-3, wherein the second value is obtained by one or more of: (i) averaging the scores from at least one or two assessments indicative of verbal learning and delayed recall, combined with at least one or two assessments indicative of visual learning and delayed recall; (ii) averaging the scores at least one or two components of a Selective Reminding Test (SRT) and at least one or two components of a Brief Visuospatial memory Test (BVMT); or (iii) calculating the second value using the following equation: [SRT learning score+SRT delay score+BVMT learning score and BVMT delay score]/4.
 5. The method of any of claims 1-4, wherein the first and the second values are weighed equally in generating the value of the composite parameter.
 6. The method of any of claims 1-4, wherein the first and the second values are weighed differentially, e.g., said first or second value being about 10%, 20%, 25%, 30%, 40%, 60%, 75% or more the value of the other value, in generating the value of the composite parameter.
 7. The method of any of claims 1-4, wherein the scores from the assessments used to obtain the second value are weighed equally.
 8. The method of any of claims 1-4, wherein the scores from the assessments used to obtain the second value are weighed differentially, e.g., said first or second value being about 10%, 20%, 25%, 30%, 40%, 60%, 75% or more the value of the other value, in generating the value of the composite parameter.
 9. The method of any of claims 1-4, wherein the scores from the assessments of verbal and visual memory are weighed equally.
 10. The method of any of claim 1-4 or 9, wherein the scores from the assessments of learning and delayed recall components are weighed equally.
 11. The method of any of claims 3-10, wherein the scores from the at least one assessment of complex scanning and/or visual tracking, and the at least one or two assessment(s) of processing speed, flexibility and/or calculation ability are weighed equally.
 12. The method of any of claims 3-10, wherein the scores from the at least one assessment of complex scanning and/or visual tracking, and the at least one or two assessment(s) of processing speed, flexibility and/or calculation ability are weighed differentially, e.g., said first or second value being about 10%, 20%, 25%, 30%, 40%, 60%, 75% or more the value of the other value, in generating the value of the composite parameter.
 13. The method of any of claims 1-12, wherein the assessments are administered simultaneously or within the same evaluation interval in the subject.
 14. The method of any of claims 1-13, wherein the reference value is acquired from: a healthy subject or an average of healthy subjects; the subject prior to, during, or after the MS therapy; the subject at two, three or more time intervals; or at least two or more MS patients having the same or different disease progressions.
 15. The method of any of claims 1-13, wherein the subject is monitored in one or more of the following periods: prior to beginning of treatment; during the treatment; after the treatment has been administered; or at a first and second time points at least 1, 2, 3, 4, 5, or 6 months apart.
 16. The method of any of claims 1-15, wherein the value of the composite parameter has a reliability of at least 0.65, 0.69, 0.70, 0.75, 0.80, 0.85, 0.90 or higher.
 17. The method of any of claims 1-16, wherein the scores are demographically adjusted.
 18. The method of any of claims 1-17, wherein the reference value is
 0. 19. The method of any of claims 1-18, wherein the value of the composite parameter ranges from −0.1 to −2 in a subject with MS.
 20. The method of any of claims 1-18, wherein a composite value of −1.5 or −1.0 SD below a reference value is indicative of cognitive impairment.
 21. The method of any of claims 1-20, wherein an increase in the value of the composite parameter, relative to the reference value, by at least 5%, 10%, 20%, 30%, 40%, 50%, or 0.2 to 1.5 SD, or more is indicative of improved cognitive function in the subject.
 22. The method of any of claims 1-20, wherein a decrease in the value of the composite parameter, relative to the reference value, by at least 5%, 10%, 20%, 30%, 40%, 50%, or 0.2 to 1.5 SD, or more is indicative of decreased cognitive function in the subject.
 23. The method of claim 3 or 4, wherein the value of the composite parameter comprises a score value chosen from one or more of: −0.6 to −1.6 for SDMT, −0.2 to −1.2 for PASAT 3, −0.12 to −1.12 for PASAT 2, −0.25 to −1.25 for SRT Total, −0.3 to −1.3 for SRT Delay, −0.8 to −1.8 for BVMT-R Total, or −1.2 to −2.2 for BVMTR Delay.
 24. The method of any of claims 1-23, wherein the value of the composite parameter is lower in a patient having secondary progressive multiple sclerosis (SPMS) compared to a patient with relapse remitting multiple sclerosis (RRMS).
 25. The method of any of claims 1-23, wherein the subject is a patient having one of: benign MS, relapse/remitting MS (RRMS), primary progressive MS, secondary progressive MS (SPMS), clinically isolated syndrome (CIS), or clinically defined MS (CDMS).
 26. The method of any of claims 1-23, wherein the subject has quiescent RRMS or active RRMS.
 27. The method of any of claims 1-23, wherein the subject has secondary progressive MS (SPMS).
 28. The method of any of claims 1-27, further comprising evaluating additional parameters chosen from one or more of quality of life, neuropsychological evaluation, or memory function.
 29. The method of any of claims 1-28, further comprising one or more steps of: performing a neurological examination, evaluating the subject's status on the Expanded Disability Status Scale (EDSS), or detecting the subject's lesion status as assessed using an MRI.
 30. The method of any of claims 2-29, wherein said method further comprises treating, or preventing in, the subject having multiple sclerosis MS one or more symptoms associated with MS by administering to a subject an MS therapy, in an amount sufficient to reduce one or more symptoms associated with MS.
 31. The method of claim 30, wherein said treating or preventing comprises reducing, retarding or preventing, a relapse, or the worsening of a disability, in the MS subject.
 32. The method of any of claims 2-29, wherein responsive to the value of the composite parameter, said method further comprises one or more of: (i) identifying the subject as being in need of a first MS therapy or a second (alternative) MS therapy; (ii) identifying the subject as having an increased or a decreased response to a first MS therapy or a second (alternative) MS therapy; (iii) identifying the subject as being stable, showing an improvement in cognitive abilities, or showing a decline in cognitive abilities; (iv) diagnosing, and/or prognosing the subject; (v) selecting or altering the course of, an MS therapy or treatment, a dose, a treatment schedule or time course, and/or the use of an alternative MS therapy; (vi) determining a time course of MS disease progression in the subject; or (vii) administering a first MS therapy or a second (alternative) MS therapy to the subject; or (viii) administering to the subject a therapy for the management of cognitive and/or memory impairment.
 33. The method of any of claims 1-32, wherein the MS therapy comprises one or more of an IFN-β1 molecule; a polymer of glutamic acid, lysine, alanine and tyrosine; an antibody or fragment thereof against alpha-4 integrin; an anthracenedione molecule; a fingolimod; a dimethyl fumarate; an antibody to the alpha subunit of the IL-2 receptor of T cells; an antibody against CD52 or alemtuzumab; an inhibitor of a dihydroorotate dehydrogenase or teriflunomide; or an anti-LINGO-1 antibody.
 34. The method of claim 33, wherein the IFN-β1 molecule comprises one or more of an IFN-β1a or IFN-β1b polypeptide, a variant, a homologue, a fragment or a pegylated variant thereof.
 35. The method of any of claims 1-32, wherein the MS therapy comprises an IFN-1b molecule; a polymer of glutamic acid, lysine, alanine and tyrosine; or the MS therapy comprises an alternative MS therapy chosen from an antibody or fragment thereof against alpha-4 integrin; a dimethyl fumarate; an anthracenedione molecule; a fingolimod; a dimethyl fumarate; an antibody to the alpha subunit of the IL-2 receptor of T cells; or an anti-LINGO-1 antibody.
 36. The method of any of claims 1-35, further comprising memorializing the value of the composite parameter, and/or providing a report comprising the memorialization.
 37. A system for evaluating and/or quantifying cognitive function in a subject having multiple sclerosis (MS), or at risk of developing MS, comprising: at least one processor operatively connected to a memory, the at least one processor when executing is configured to: establish a value of a composite parameter associated with the subject indicative of cognitive function, wherein the at least one processor is further configured to establish the value of the composite parameter responsive to establishing a first value for an attention and/or processing speed (PS) factor and a second value for a memory factor, wherein the at least one processor when executing is configured to: compute an average value of scores from at least two assessments indicative of attention and/or processing speed to determine the first value, and compute an average value of scores from at least one assessment of auditory/verbal learning and memory, and a score from at least one assessment of visual learning and memory to determine the second value; compute the value of the composite parameter from a combination of the first and second values; (optionally) compare the value of the composite parameter from the subject to a reference value, and identify an indication of improved cognitive function in the subject, wherein identifying the indication of improved cognitive function includes detecting an increase in the value of the composite parameter, relative to a reference value; or identify an indication of decreased cognitive function in the subject, wherein identifying the indication of decreased cognitive function includes detecting a decrease in the value of the composite parameter, relative to the reference value.
 38. The system of claim 37, wherein the at least one processor when executing is configured to determine at least a portion of the first value by performing one or more of: (i) compute an average value of the scores from at least one assessment of complex scanning and/or visual tracking, and the average value from at least one or two assessment(s) of processing speed, flexibility and/or calculation ability; (ii) compute a function of a score based on a Symbol Digit Modalities Test (SMDT)) and a function of a score based on at least one or two Paced Auditory Serial Addition Test (PASAT); or (iii) compute the first value based on determining a value for the equation ((Symbol Digit Modalities Test (SDMT) score+(a first Paced Auditory Serial Addition Test (“PASAT”) score (e.g., PASAT 3″) and a second PASAT score (e.g., PASAT 2″))/2)/2.
 39. The system of either of claim 37 or 38, wherein the at least one processor when executing is configured to determine at least a portion of the second value by performing one or more of: (i) compute an average value of the scores from at least one or two assessments indicative of verbal learning and delayed recall, and the average value of at least one or two assessments indicative of visual learning and delayed recall; (ii) compute an average value of the scores from at least one or two components of a Selective Reminding Test (SRT) and at least one or two components of a Brief Visuospatial memory Test (BVMT); or (iii) compute the second value based on determining a value for the equation: [SRT learning score+SRT delay score+BVMT learning score and BVMT delay score]/4.
 40. The system of any of claims 37-39, wherein the at least one processor when executing is further configured to: compute a reliability value for the composite parameter, and evaluate the reliability value against a minimum threshold parameter including at least one of the threshold parameter set for at least 0.65, 0.69, 0.70, 0.75, 0.80, 0.85 or higher.
 41. The system of any of claims 37-40, wherein the at least one processor when executing is further configured to weigh equally the first and the second values.
 42. The system of any of claims 37-40, wherein the at least one processor when executing is further configured to weigh differentially the first and the second values, e.g., said first or second value being about 10%, 20%, 25%, 30%, 40%, 60%, 75% or more the value of the other value.
 43. The system of any of claims 37-40, wherein the at least one processor when executing is further configured to weigh equally the scores from the assessments used to obtain the second value.
 44. The system of any of claims 37-40, wherein the at least one processor when executing is further configured to weigh differentially the scores from the assessments used to obtain the second value, e.g., said first or second value being about 10%, 20%, 25%, 30%, 40%, 60%, 75% or more the value of the other value.
 45. The system of any of claims 37-40, wherein the at least one processor when executing is further configured to weigh equally the scores from the assessments of verbal and visual memory.
 46. The system of any of claim 37-40 or 45, wherein the at least one processor when executing is further configured to weigh equally the scores from the assessments of learning and delayed recall components.
 47. The system of any of claims 38-46, wherein the at least one processor when executing is further configured to weigh equally the scores from the at least one assessment of complex scanning and/or visual tracking, and the scores from the at least one or two assessment(s) of processing speed, flexibility and/or calculation ability.
 48. The system of any of claims 38-46, wherein the at least one processor when executing is further configured to weigh differentially the scores from the at least one assessment of complex scanning and/or visual tracking, and the scores from the at least one assessment of complex scanning and/or visual tracking, e.g, said first or second value being about 10%, 20%, 25%, 30%, 40%, 60%, 75% or more the value of the other value.
 49. The system of any of claims 37-48, wherein the at least one processor is configured to evaluate the composite parameter against a probabilistic model of a time course progression of disease effect on cognition for the subject, wherein the probabilistic model includes the reference value.
 50. The system of any of claims 37-48, wherein the at least one processor is configured to generate the probabilistic model of the time course progression of the disease effect on cognition for the subject including a time course of the reference value.
 51. The system of claim 50, wherein the at least one processor is configured to generate the probabilistic model from at least one or more of: a healthy subject; a group of healthy subjects; the subject prior to, during, or after the MS therapy; a group of MS patients having the same disease progressions; a group of MS patients having different disease progressions; a group of MS patients having the same or different disease progressions at different time intervals; a group of MS patients undergoing different MS treatments than the subject; or a group of MS patients undergoing a same MS treatment as the subject.
 52. The system of claim 51, wherein the at least one processor is configured to identify patients having similar MS disease progression from a model population.
 53. The system of claim 50, wherein the at least one processor is configured to: compute a SRT Total Learning value, SRT Delayed Recall value, BVMT Total Recall value, BVMT Delayed Recall value to establish a memory factor portion for the reference value; compute a SDMT value, a first PASAT, a second PASAT value to establish an attention factor portion; and compute a combination of the memory factor portion and the attention factor portion to obtain the reference value.
 54. The system of any of claims 37-53, wherein the at least one processor when executing is further configured to perform one or more of: comparing the value of the composite parameter from the subject to a reference value for a time parameter defined for a course of MS progression; identifying the subject as being in need of an MS therapy; recommending administration of an MS therapy; determining or altering a dosing of the MS therapy; determining or altering a schedule or a time course of the MS therapy; and recommending an alternative MS therapy.
 55. The system of any of claims 37-53, wherein the at least one processor when executing is further configured to: capture a plurality of values of the composite parameter for the subject over time, and generate a model of the time course progression of the composite parameter, wherein the model is reflective of a disease state of the subject having MS.
 56. A computer implemented method for evaluating disease progression in a subject having multiple sclerosis (MS), or at risk for developing MS, the method comprising: establishing, by a computer system, a value of a composite parameter associated with the subject indicative of cognitive function, wherein establishing the value of the composite parameter includes establishing a first value for an attention and/or processing speed (PS) factor and a second value for a memory factor, computing, by a computer system, an average value of scores from at least two assessments indicative of attention and/or processing speed to determine the first value, and computing, by a computer system, an average value of scores from at least one assessment of auditory/verbal learning and memory, and a score from at least one assessment of visual learning and memory to determine the second value; computing, by a computer system, the value of the composite parameter from a combination of the first and second values; (optionally) comparing, by the computer system, the value of the composite parameter from the subject to a reference value, and identifying, by the computer system, an indication of improved cognitive function in the subject, wherein identifying the indication of improved cognitive function includes detecting an increase in the value of the composite parameter, relative to a reference value; or identifying, by the computer system, an indication of decreased cognitive function in the subject, wherein identifying the indication of decreased cognitive function includes detecting a decrease in the value of the composite parameter, relative to the reference value.
 57. The method of claim 56, wherein establishing the first value for the subject comprises one or more of: (i) computing an average value of the scores from at least one assessment of complex scanning and/or visual tracking, and at least one or two assessment(s) of processing speed, flexibility and/or calculation ability; (ii) computing an average value of a score based on a Symbol Digit Modalities Test (SMDT)) and a score based on at least one or two Paced Auditory Serial Addition Test (PASAT); or (iii) computing the first value based on determining a value for the following equation: {SMDT score+[PASAT 3 score+PASAT 2 score]/2)}/2.
 58. The method of either of claim 56 or 57, wherein establishing the second value for the subject comprises one or more of: (i) computing an average value of the scores from at least one or two assessments indicative of verbal learning and delayed recall, combined with at least one or two assessments indicative of visual learning and delayed recall; (ii) computing an average value of a score from at least one or two components of a Selective Reminding Test (SRT) and at least one or two components of a Brief Visuospatial memory Test (BVMT); or (iii) computing the second value based on determining a value for the following equation: [SRT learning score+SRT delay score+BVMT learning score and BVMT delay score]/4.
 59. The method of any of claims 56-58, wherein the establishing the value of the composite value includes weighing the first and the second values equally.
 60. The method of any of claims 56-58, wherein the establishing the value of the composite value includes weighing the first and the second values differentially, e.g., said first or second value being about 10%, 20%, 25%, 30%, 40%, 60%, 75% or more the value of the other value, in generating the value of the composite parameter.
 61. The method of any of claims 56-58, wherein the establishing the second value includes weighing the scores from the assessments used to obtain the second value are weighed equally.
 62. The method of any of claims 56-58, wherein the establishing the second value includes weighing the scores from the assessments used to obtain the second value are weighed differentially, e.g., said first or second value being about 10%, 20%, 25%, 30%, 40%, 60%, 75% or more the value of the other value, in generating the value of the composite parameter.
 63. The method of any of claims 56-58, wherein the establishing the second value includes weighing the scores from the assessments of verbal and visual memory equally.
 64. The method of any of claim 56-58 or 63, wherein the establishing the second value includes weighing equally the scores from the assessments of learning and delayed recall components.
 65. The method of any of claims 56-64, wherein the establishing the second value includes weighing equally the scores from at least one assessment of complex scanning and/or visual tracking, and at least one or two assessment(s) of processing speed, flexibility and/or calculation ability.
 66. The method of any of claims 56-64, wherein the establishing the second value includes weighing the scores from at least one assessment of complex scanning and/or visual tracking, and the at least one or two assessment(s) of processing speed, flexibility and/or calculation ability differentially, e.g., said first or second value being about 10%, 20%, 25%, 30%, 40%, 60%, 75% or more the value of the other value.
 67. The method any of claims 56-58, wherein computing at least the portion of the second value includes computing at least the portion of the second value based on determining a value for the equation (Brief Visuospatial Memory Test (“BVMT”) Total Recall value+BVMT Delayed Recall value)/2.
 68. The method any of claims 56-58, wherein computing at least the portion of the second value includes determining the average of the value of a verbal memory factor and a visual memory factor from the equation ((SRT Total Learning value+SRT Delayed Recall value)/2+(BVMT Total Recall value+BVMT Delayed Recall value)/2)/2.
 69. The method of any of claims 56-58, wherein the establishing the value of the composite parameter includes computing the composite parameter from the average of the value of the verbal memory factor and the visual memory factor averaged with the attention factor value calculated from the equation ((SDMT value+(PASAT 3 and PASAT 2)/2)/2.
 70. The method of any of claims 56-69, further comprising: computing a reliability value for the composite parameter, and evaluating the reliability value against a minimum threshold parameter including at least one of the threshold parameter set for at least 0.65, 0.69, 0.70, 0.75, 0.80, 0.85 or higher.
 71. The system or method of any of claims 37-, further comprising: storing the value of the composite parameter, and generating a report including analysis of the stored composite value, wherein the analysis is reflective of a status of the subject having MS.
 72. A kit for evaluating an MS patient, comprising: a means or tests for evaluating one, two, three, four or more attention and memory factors chosen from: (i) an assessment of processes involved in learning and/or remembering visual information, (ii) an assessment of visuospatial memory, (iii) an assessment of complex scanning and/or visual tracking, or (iv) an assessment of one or more of auditory information processing speed, flexibility or calculation ability; and a means for determining a value of a composite parameter associated with the subject, prior to, during, and/or after an MS therapy. 